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Emergence of a game changer in the field of medical microrobots. Development of a mass production method for biodegradable microrobots that can disappear into the body after delivering cells and drugs.

  • 조회. 457
  • 등록일. 2022.10.09
  • 작성자. External Relations Team

- Microrobots disintegrate in the body after delivering stem cells to the target point, and the delivered stem cells are verified to be capable of normal proliferation and differentiation.

- Expected to contribute to increasing the efficiency of regenerative medicine such as stem cell delivery.

 Daegu Gyeongbuk Institute of Science & Technology (DGIST, President Yang Kook) Professor Hongsoo Chois team of the Department of Robotics and Mechatronics Engineering collaborated with Professor Sung-Won Kims team at Seoul St. Marys Hospital, Catholic University of Korea, and Professor Bradley J. Nelsons team at ETH Zurich to develop a technology that produces more than 100 microrobots per minute that can be disintegrated in the body.

 Microrobots aiming at minimal invasive targeted precision therapy can be manufactured in various ways. Among them, ultra-fine 3D printing technology called two-photon polymerization method, a method that triggers polymerization by intersecting two lasers in synthetic resin, is the most used. This technology can produce a structure with nanometer-level precision. However, a disadvantage exists in that producing one microrobot is time consuming because voxels, the pixels realized by 3D printing, must be cured successively. In addition, the magnetic nanoparticles contained in the robot can block the light path during the two-photon polymerization process.  This process result may not be uniform when using magnetic nanoparticles with high concentration.

 To overcome the limitations of the existing microrobot manufacturing method, DGIST Professor Hongsoo Chois research team developed a method to create microrobots at a high speed of 100 per minute by flowing a mixture of magnetic nanoparticles and gelatin methacrylate, which is biodegradable and can be cured by light, into the microfluidic chip. This is more than 10,000 times faster than using the existing two-photon polymerization method to manufacture microrobots.

 Then, the microrobot produced with this technology was cultured with human nasal turbinated stem cells collected from human nose to induce stem cell adherence to the surface of the microrobot. Through this process, a stem cell carrying microrobot, including magnetic nanoparticles inside and stem cells attached to the exterior surface, was fabricated. The robot moves as the magnetic nanoparticles inside the robot respond to an external magnetic field and can be moved to a desired position.

 Selective cell delivery was difficult in the case of the existing stem cell therapy. However, the stem cell carrying microrobot can move to a desired location by controlling the magnetic field generated from the electromagnetic field control system in real time. The research team conducted an experiment to examine whether the stem cell carrying microrobot could reach the target point by passing through a maze-shaped microchannel, and consequently confirmed that the robot could move to the desired location.

 In addition, the degradability of the microrobot was evaluated by incubating the stem cell carrying microrobot with degrading enzyme. After 6 h of incubation, the microrobot was completely disintegrated, and the magnetic nanoparticles inside the robot were collected by the magnetic field generated from the magnetic field control system. Stem cells were proliferated at the location where the microrobot was disintegrated. Subsequently, the stem cells were induced to differentiate into nerve cells to confirm normal differentiation; the stem cells were differentiated into nerve cells after approximately 21 days. This experiment verified that delivering stem cells to a desired location using a microrobot was possible and that the delivered stem cells could serve as a targeted precision therapeutic agent by exhibiting proliferation and differentiation.

 Furthermore, the research team confirmed whether the stem cells delivered by the microrobot exhibited normal electrical and physiological characteristics. The final goal of this study is to ensure that the stem cells delivered by the robot normally perform their bridge role in a state where the connection between the existing nerve cells is disconnected. To confirm this, hippocampal neurons extracted from rat embryo that stably emit electrical signals were utilized. The corresponding cell was attached to the surface of the microrobot, cultured on a micro-sized electrode chip, and electrical signals were observed from the hippocampal neurons after 28 days. Through this, the microrobot was verified to properly perform its role as a cell delivery platform.

 DGIST Professor Hongsoo Choi said, We expect that the technologies developed through this study, such as mass production of microrobots, precise operation by electromagnetic fields, and stem cell delivery and differentiation, will dramatically increase the efficiency of targeted precision therapy in the future.

 Meanwhile, the results of this study were published on June 23 in the world-renowned international scientific journal Small (top 7.10% in the Multidisciplinary) and was carried out with the support of the National Science Challenges Support & Network, National Research Foundation of Korea, and the Ministry of Science and ICT.

 

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Summary of Research Results

A Biodegradable magnetic microrobot based on gelatin methacrylate for precise delivery of stem cells with mass production capability

Seungmin Noh, Sungwoong Jeon, Eunhee Kim, Untaek Oh, Danbi Park, Sun Hwa Park, Sung Won Kim, Salvador Pane, Bradley J. Nelson, Jin-young Kim, Hongsoo Choi

(Small, 2022, 2107888, June 23, 2022)

 

 Stem cell therapy can restore lost functions by differentiating into specific cells in the damaged area. However, the existing stem cell delivery methods, such as intravenous injection and surgical transplantation, had problems such as infection, migration of stem cells to other sites, and low transfer efficiency. To solve these problems, considerable research has been conducted on cell delivery using microrobots, and to date, many microrobots have been manufactured using a method called two-photon polymerization. However, producing large numbers of microrobots was difficult using the two-photon polymerization method owing to low production efficiency. Furthermore, the number of magnetic nanoparticles was limited because the magnetic nanoparticles contained inside blocked the light path, and therefore, increasing the low thrust of the robot was difficult.

 

In this study, to solve these problems, the microfluidic chip was used to considerably improve the manufacturing efficiency of the microrobot, and the magnetic nanoparticle concentration inside the robot was also increased. Human nasal-derived stem cells were attached to the surface of the developed microrobot to act as a stem cell carrier. After moving to the target site, the microrobot was verified to be melted by the enzyme, and the stem cells were verified to be simultaneously selectively transferred. These delivered stem cells showed potential as a cell carrier for microrobots by exhibiting proliferation and differentiation into neurons at the target site. Finally, hippocampal cells extracted from rat embryo were similarly attached to the surface of the robot and cultured on a microelectrode array, and electrophysiological signals were measured to show that the microrobot did not affect cell characteristics. The biodegradable microrobot developed in this study is expected to be applied to targeted precision stem cell therapy.

 

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Q&A for Research Results

Q. What is different about this achievement?

Typical stem cell therapy methods include intravenous injection and surgical transplantation, but they have problems such as low delivery efficiency, stem cell migration, and infection. Microrobot research started as a method to solve these problems. Microrobot research for cell delivery through magnetic field driving that can deliver cells to desired locations was reported for the first time in the world by this research team. (Kim et al., Advanced Materials, 2013). Subsequently, we developed helical and spherical microrobots for stem cell delivery and showed it differentiating into various cells. (Jeon et al., Science Robotics, 2019)

 In previous studies, the focus of the study was to evaluate the potential by proving the concept of magnetic field driven microrobot for cell delivery for the first time and to determine whether the delivering cell functions normally. However, existing robots are difficult to apply to clinical practice in that manufacturing one microrobot takes several tens of minutes to several hours. This study is a follow-up study to the previous study, and this study aims to fabricate the microrobot using gelatin methacrylate (hereafter, GelMA), a biodegradable material, and to considerably increase the efficiency of robot manufacturing. The research team produced more than 100 spherical microrobots per minute that can be disintegrated in the body, showing a production speed 10,000 times faster than that of the existing production method. The effectiveness and safety of the microrobot as a stem cell carrier was evaluated through proliferation of cells attached to the microrobot and differentiation into nerve cells. Although microrobot research itself must be conducted for a long time in the future, this study is expected to considerably improve production efficiency and bring it one step closer to actual clinical application.

Q. Where can it be used?

The degradable magnetic microrobot developed by the research team was used to deliver stem cells in this study. These robots can be used to precisely deliver cells to locations, such as knees, brain, and liver, where delivering cells with hands or surgical tools is difficult. In addition, this robot is expected to play a role as the drug deliverer by placing drugs, such as anticancer drugs, inside microrobots during the manufacturing process.

Q. How long does it require for implementation?

 Microrobot research field itself started recently, including this study, and the practical application of medical microrobots implies their application to the human body; hence, achieving practical application in a short period of time is difficult. However, if institutional support, such as approval, or clinical research related to advanced regenerative medicine, such as the recently enacted Advanced Regenerative Bio Act, exists, this time can be accelerated.

Q. What are the tasks for practical use?

 For the practical application of microrobots, research on magnetic field control systems, real-time imaging systems, and therapeutic agent delivery microrobots should be accompanied. Although many studies have been conducted on magnetic field control systems and therapeutics delivery microrobots even to be used in animal experiments, more research is required to accurately identify the position of nano-micro-sized robots in the body. Recently, studies on imaging the position of microrobots in the body are being conducted, but the technology is thought to be not advanced enough to be practical for clinical use.

 Moreover, for technology advancement and commercialization, technology development and clinical trials are required. It is expected to receive considerable assistance through active support from government departments.

Q. What was the reason for starting the study?

The research team started related studies in 2011 with the goal of developing microrobots that can precisely minimally invasively deliver cells to the target site. To overcome the limitations of extensive exposure and invasively conventional stem cell delivery, microrobots that can deliver cells to a target location by external magnetic field were developed. Beginning with the first original research results (Kim et al., Advanced Materials, 2013, Cover paper) in 2013, technology was advanced through cell delivery research with various types of microrobots. (Lee et al., Advanced Healthcare Materials, 2020/Jeon et al., Science Robotics, 2019)

Q. What meaning does it convey?

The microrobot production and stem cell delivery methods developed by the research team are meaningful in that we use materials that can be disintegrated in the body and considerably increase the production efficiency of microrobots that have been previously manufactured with low efficiency. In addition, because microrobots were manufactured using easily fabricated microfluidic chips, notably, the barriers of entry for new researchers into microrobot research have also been lowered.

Q. What do you aim to achieve eventually?

 In this study, the precise delivery of cells attached to the microrobot to the target site was verified, and the intrinsic properties of cells such as proliferation and differentiations were noted to be unchanged. Further, through additional research, animal experiments using microrobots were conducted to show that microrobots had a therapeutic effect on lesions such as joints and brain. Finally, microrobots that are effective enough to be used in actual stem cell therapy such as knee diseases and brain diseases are expected to be developed, even if this is not the result of this study.

 

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Figures Description

[Figure 1]

Mass production method of microrobots using microfluidic chips (top) and Response of the manufactured microrobot to the external magnetic field (magnet) (bottom)

 

[Figure 2]

The 24-h process of stem cells attaching to the microrobot surface (top) and Cell staining results to identify cells attached to the microrobot surface (bottom)

 

[Figure 3]

Precise control of stem cell carrying microrobots in a sophisticated maze and the writing of the word MR (top), Disintegration of microrobot by enzyme and collection of magnetic nanoparticles from the robot (middle), Attachment and proliferation of stem cells delivered via the robot (bottom)

 

[Figure 4]

Cell staining to verify the differentiation of stem cells delivered to the target site into neurons (top), Verification of electrical signals generated from hippocampal neurons attached to microrobots (bottom)

 

 

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For more information, contact:
Choi, Hongsoo
Department of Robotics and Mechatronics Engineering
Daegu Gyeongbuk Institute of Science and Technology (DGIST)
E-mail: mems@dgist.ac.kr

Associated Links
Research Paper on Small 
https://doi.org/10.1002/smll.202107888

Journal Reference
Seungmin Noh,Sungwoong Jeon,Eunhee Kim,Untaek Oh,Danbi Park,Sun Hwa Park,Sung Won Kim,Salvador Pané,Bradley J. Nelson,Jin-young Kim,Hongsoo Choi, "A Biodegradable Magnetic Microrobot Based on Gelatin Methacrylate for Precise Delivery of Stem Cells with Mass Production Capability", online published on 06.23,2022.