MERS
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KAIST presents strategies for Holotomography in advanced bio research
Measuring and analyzing three-dimensional (3D) images of live cells and tissues is considered crucial in advanced fields of biology and medicine. Organoids, which are 3D structures that mimic organs, are particular examples that significantly benefits 3D live imaging. Organoids provide effective alternatives to animal testing in the drug development processes, and can rapidly determine personalized medicine. On the other hand, active researches are ongoing to utilize organoids for organ replacement.
< Figure 1. Schematic illustration of holotomography compared to X-ray CT. Similar to CT, they share the commonality of measuring the optical properties of an unlabeled specimen in three dimensions. Instead of X-rays, holotomography irradiates light in the visible range, and provides refractive index measurements of transparent specimens rather than absorptivity. While CT obtains three-dimensional information only through mechanical rotation of the irradiating light, holotomography can replace this by applying wavefront control technology in the visible range. >
Organelle-level observation of 3D biological specimens such as organoids and stem cell colonies without staining or preprocessing holds significant implications for both innovating basic research and bioindustrial applications related to regenerative medicine and bioindustrial applications.
Holotomography (HT) is a 3D optical microscopy that implements 3D reconstruction analogous to that of X-ray computed tomography (CT). Although HT and CT share a similar theoretical background, HT facilitates high-resolution examination inside cells and tissues, instead of the human body. HT obtains 3D images of cells and tissues at the organelle level without chemical or genetic labeling, thus overcomes various challenges of existing methods in bio research and industry. Its potential is highlighted in research fields where sample physiology must not be disrupted, such as regenerative medicine, personalized medicine, and infertility treatment.
< Figure 2. Label-free 3D imaging of diverse live cells. Time-lapse image of Hep3B cells illustrating subcellular morphology changes upon H2O2 treatment, followed by cellular recovery after returning to the regular cell culture medium. >
This paper introduces the advantages and broad applicability of HT to biomedical researchers, while presenting an overview of principles and future technical challenges to optical researchers. It showcases various cases of applying HT in studies such as 3D biology, regenerative medicine, and cancer research, as well as suggesting future optical development. Also, it categorizes HT based on the light source, to describe the principles, limitations, and improvements of each category in detail. Particularly, the paper addresses strategies for deepening cell and organoid studies by introducing artificial intelligence (AI) to HT.
Due to its potential to drive advanced bioindustry, HT is attracting interest and investment from universities and corporates worldwide. The KAIST research team has been leading this international field by developing core technologies and carrying out key application researches throughout the last decade.
< Figure 3. Various types of cells and organelles that make up the imaging barrier of a living intestinal organoid can be observed using holotomography. >
This paper, co-authored by Dr. Geon Kim from KAIST Research Center for Natural Sciences, Professor Ki-Jun Yoon's team from the Department of Biological Sciences, Director Bon-Kyoung Koo's team from the Institute for Basic Science (IBS) Center for Genome Engineering, and Dr. Seongsoo Lee's team from the Korea Basic Science Institute (KBSI), was published in 'Nature Reviews Methods Primers' on the 25th of July. This research was supported by the Leader Grant and Basic Science Research Program of the National Research Foundation, the Hologram Core Technology Development Grant of the Ministry of Science and ICT, the Nano and Material Technology Development Project, and the Health and Medical R&D Project of the Ministry of Health and Welfare.
2024.07.30 View 1586 -
KAIST develops biocompatible adhesive applicable to hair transplants
Aside from being used as a new medical adhesive, the new material can be applied to developing a new method of hair transplants, which cannot be repeated multiple times using current method of implanting the wholly intact follicles into the skin.
Medical adhesives are materials that can be applied to various uses such as wound healing, hemostasis, vascular anastomosis, and tissue engineering, and is expected to contribute greatly to the development of minimally invasive surgery and organ transplants. However, adhesives with high adhesion, low toxicity, and capable of decomposing in the body are rare. Adhesives based on natural proteins, such as fibrin and collagen, have high biocompatibility but insufficient adhesive strength. Synthetic polymer adhesives based on urethane or acrylic have greater adhesion but do not decompose well and may cause an inflammatory reaction in the body.
A joint research team led by Professor Myungeun Seo and Professor Haeshin Lee from the KAIST Department of Chemistry developed a bio-friendly adhesive from biocompatible polymers using tannic acid, the source of astringency in wine.
The research team focused on tannic acid, a natural polyphenolic product. Tannic acid is a polyphenol present in large amounts in fruit peels, nuts, and cacao. It has a high affinity and coating ability on other substances, and we sense the astringent taste in wine when tannic acid sticks to the surface of our tongue. When tannic acid is mixed with hydrophilic polymers, they form coacervates, or small droplets of jelly-like fluids that sink. If the polymers used are biocompatible, the mixture can be applied as a medical adhesive with low toxicity. However, coacervates are fundamentally fluid-like and cannot withstand large forces, which limits their adhesive capabilities. Thus, while research to utilize it as an adhesive has been actively discussed, a biodegradable material exhibiting strong adhesion due to its high shear strength has not yet been developed.
The research team figured out a way to enhance adhesion by mixing two biocompatible FDA-approved polymers, polyethylene glycol (PEG) and polylactic acid (PLA). While PEG, which is used widely in eyedrops and cream, is hydrophilic, PLA, a well-known bioplastic derived from lactic acid, is insoluble in water. The team combined the two into a block copolymer, which forms hydrophilic PLA aggregates in water with PEG blocks surrounding them. A coacervate created by mixing the micelles and tannic acid would behave like a solid due to the hard PLA components, and show an elastic modulus improved by a thousand times compared to PEG, enabling it to withstand much greater force as an adhesive.
Figure 1. (Above) Principle of biodegradable adhesive made by mixing poly(ethylene glycol)-poly(lactic acid) diblock copolymer and tannic acid in water. Yellow coacervate is precipitated through hydrogen bonding between the block copolymer micelles and tannic acid, and exhibits adhesion. After heat treatment, hydrogen bonds are rearranged to further improve adhesion. (Bottom) Adhesion comparison. Compared to using poly(ethylene glycol) polymer (d), it can support 10 times more weight when using block copolymer (e) and 60 times more weight after heat treatment (f). The indicated G' values represent the elastic modulus of the material.
Furthermore, the research team observed that the material’s mechanical properties can be improved by over a hundred times through a heating and cooling process that is used to heat-treat metals. They also discovered that this is due to the enforced interactions between micelle and tannic acid arrays.
The research team used the fact that the material shows minimal irritation to the skin and decomposes well in the body to demonstrate its possible application as an adhesive for hair transplantation through an animal experiment. Professor Haeshin Lee, who has pioneered various application fields including medical adhesives, hemostatic agents, and browning shampoo, focused on the adhesive capacities and low toxicity of polyphenols like tannic acid, and now looks forward to it improving the limitations of current hair transplant methods, which still involve follicle transfer and are difficult to be repeated multiple times.
Figure 2. (a) Overview of a hair transplantation method using a biodegradable adhesive (right) compared to a conventional hair transplantation method (left) that transplants hair containing hair follicles. After applying an adhesive to the tip of the hair, it is fixed to the skin by implanting it through a subcutaneous injection, and repeated treatment is possible. (b) Initial animal test results. One day after 15 hair transplantation, 12 strands of hair remain. If you pull the 3 strands of hair, you can see that the whole body is pulled up, indicating that it is firmly implanted into the skin. All strands of hair applied without the new adhesive material fell off, and in the case of adhesive without heat treatment, the efficiency was 1/7.
This research was conducted by first co-authors Dr. Jongmin Park (currently a senior researcher at the Korea Research Institute of Chemical Technology) from Professor Myeongeun Seo’s team and Dr. Eunsook Park from Professor Haeshin Lee’s team in the KAIST Department of Chemistry, and through joint research with the teams led by Professor Hyungjun Kim from the KAIST Department of Chemistry and Professor Siyoung Choi from the Department of Chemical and Biomolecular Engineering. The research was published online on August 22 in the international journal Au (JACS Au) under the title Biodegradable Block Copolymer-Tannic Acid Glue.
This study was funded by the Support Research Under Protection Project of the National Research Foundation (NRF), Leading Research Center Support Project (Research Center for Multiscale Chiral Structure), Biodegradable Plastics Commercialization and Demonstration Project by the Ministry of Trade and Industry, and institutional funding from the Korea Research Institute of Chemical Technology.
2022.10.07 View 7665 -
New Polymer Mesophase Structure Discovered
Bilayer-folded lamellar mesophase induced by random polymer sequence
Polymers, large molecules made up of repeating smaller molecules called monomers, are found in nearly everything we use in our day-to-day lives. Polymers can be natural or created synthetically. Natural polymers, also called biopolymers, include DNA, proteins, and materials like silk, gelatin, and collagen. Synthetic polymers make up many different kinds of materials, including plastic, that are used in constructing everything from toys to industrial fiber cables to brake pads.
As polymers are formed through a process called polymerization, the monomers are connected through a chain. As the chain develops, the structure of the polymer determines its unique physical and chemical properties. Researchers are continually studying polymers, how they form, how they are structured, and how they develop these unique properties. By understanding this information, scientists can develop new uses for polymers and create new materials that can be used in a wide variety of industries.
In a paper published in Nature Communications on May 4, researchers describe a new structure found in an aqueous solution of an amphiphilic copolymer, called a bilayer-folded lamellar mesophase, that has been discovered through a random copolymer sequence.
“A new mesophase is an important discovery as it shows a new way for molecules to self-organize,” said Professor Myungeun Seo at the Department of Chemistry at KAIST. “We were particularly thrilled to identify this bilayer-folded lamellar phase because pure bilayer membranes are difficult to fold thermodynamically.”
Researchers think that this mesophase structure comes from the sequence of the monomers within the copolymer. The way the different monomers arrange themselves in the chain that makes up a copolymer is important and can have implications for what the copolymer can do. Many copolymers are random, which means that their structure relies on how the monomers interact with each other. In this case, the interaction between the hydrophobic monomers associates the copolymer chains to conceal the hydrophobic domain from water. As the structure gets more complex, researchers have found that a visible order develops so that monomers can be matched up with the right pair.
“While we tend to think random means disorder, here we showed that a periodic order can spontaneously arise from the random copolymer sequence based on their collective behavior,” said Professor Seo. “We believe this comes from the sequence matching problem: finding a perfectly complementary pair for a long sequence is nearly impossible.”
This is what creates the unique structure of this newly discovered mesophase. The copolymer spontaneously folds and creates a multilamellar structure that is separated by water. A multilamellar structure refers to plate-like folds and the folded layers stack on top of each other. The resulting mesophase is birefringent, meaning light refracts through it, it is similar to liquid crystalline, and viscoelastic, which means that it is both viscous and elastic at the same time.
Looking ahead, researchers hope to learn more about this new mesophase and figure out how to control the outcome. Once more is understood about the mesophase and how it is formed, it’s possible that new mesophases could be discovered as more sequences are researched. “One of the obvious questions for us is how to control the folding frequency and adjust the folded height, which we are currently working to address. Ultimately, we want to understand how different multinary sequences can associate with another to create order and apply the knowledge to develop new materials,” said Professor Seo. The National Research Foundation, the Ministry of Education, and the Ministry of Science and ICT of Korea funded this research.
-PublicationMinjoong Shin, Hayeon Kim, Geonhyeong Park, Jongmin Park, Hyungju Ahn, Dong Ki Yoon, Eunji Lee, Myungeun Seo, “Bilayer-folded lamellar mesophase induced by random polymersequence,” May 4, 2022, Nature Communications (https://doi.org/10.1038/s41467-022-30122-z)
-ProfileProfessor Myungeun SeoMacromolecular Materials Chemistry Lab (https://nanopsg.kaist.ac.kr/)Department of ChemistryCollege of Natural SciencesKAIST
2022.06.17 View 6467 -
KAIST to support the Genetic Donguibogam Research Project for global market entry of a new natural drug produced by Green Cross Corporation HS
In the wake of the spread of the Middle East Respiratory Syndrome (MERS), sales of immune-enhancing products in Korea such as red and white ginseng have risen dramatically. Ginseng is one of Korea’s major health supplement it exports, but due to the lack of precise scientific knowledge of its mechanism, sales of ginseng account for less than 2% of the global market share.
The Genetic Donguibogam Research Project represents a group of research initiatives to study genes and environmental factors that contribute to diseases and to discover alternative treatments through Eastern medicine. The project is being led by KAIST’s Department of Bio & Brain Engineering Professor Do-Heon Lee.
Professor Lee and Chief Executive Officer Young-Hyo Yoo of Green Cross Corporation HS, a Korean pharmaceutical company, signed a memorandum of understanding (MOU), as well as a non-disclosure agreement (NDA) to develop a naturally derived drug with an enhanced ginsenoside, pharmacological compounds of ginseng, for the global market entry of BST204 on June 10, 2015.
Donguibogam is the traditional Korean source for the principles and practice of Eastern medicine, which was compiled by the royal physician Heo Jun and first published in 1613 during the Joseon Dynasty of Korea.
Cooperating with Green Cross Co., HS, KAIST researchers will use a multi-component, multi-target (MCMT)-based development platform to produce the new natural drug, BST204. This cooperation is expected to assist the entry of the drug into the European market.
Green Cross Co., HS has applied a bio-conversion technique to ginseng to develop BST204, which is a drug with enhanced active constituent of aginsenosides. The drug is the first produced by any Korean pharmaceutical company to complete the first phase of clinical trials in Germany and is about to start the second phase of trials.
Professor Do-Heon Lee, the Director of the project said, “Genetic Donguibogam Research Project seeks to create new innovative healthcare material for the future using integrated fundamental technologies such as virtual human body computer modelling and multi-omics to explain the mechanism in which natural ingredients affect the human body.” He continued, “Especially, by employing the virtual human body computer modelling, we can develop an innovative new technology that will greatly assist Korean pharmaceutical industry and make it the platform technology in entering global markets.”
Young-Hyo Yoo, the CEO of Green Cross Co., HS, said, “For a new naturally derived drug to be acknowledged in the global market, such as Europe and the US, its mechanism, as well as its effectiveness and safety, should be proven. However, it is difficult and costly to explain the mechanism in which the complex composition of a natural substance influences the body. Innovative technology is needed to solve this problem.”
Professor Do-Heon Lee (left in the picture), the Director of Genetic Donguibogam Research Project, stands abreast Young-Hyo Yoo (right in the picture), the CEO of Green Cross Co., HS.
2015.06.10 View 7758 -
Novel Photolithographic Technology Enabling 3D Control over Functional Shapes of Microstructures
Professor Shin-Hyun Kim and his research team in the Department of Chemical and Biomolecular Engineering at KAIST have developed a novel photolithographic technology enabling control over the functional shapes of micropatterns using oxygen diffusion.
The research was published online in the March 13th issue of Nature Communications and was selected as a featured image for the journal.
Photolithography is a standard optical process for transferring micropatterns on to a substrate by exposing specific regions of the photoresist layer to ultraviolet (UV) light. It is used widely throughout industries that require micropatterns, especially in the semiconductor manufacturing industry.
Conventional photolithography relied on photomasks which protected certain regions of the substrate from the input UV light. Areas covered by the photomasks remain intact with the base layer while the areas exposed to the UV light are washed away, thus creating a micropattern. This technology was limited to a two-dimensional, disc-shaped design as the boundaries between the exposed and roofed regions are always in a parallel arrangement with the direction of the light.
Professor Kim’s research team discovered that: 1) the areas exposed to UV light lowered the concentration of oxygen and thus resulted in oxygen diffusion; and 2) manipulation of the diffusion speed and direction allowed control of the growth, shape and size of the polymers. Based on these findings, the team developed a new photolithographic technology that enabled the production of micropatterns with three-dimensional structures in various shapes and sizes.
Oxygen was considered an inhibitor during photopolymerization. Photoresist under UV light creates radicals which initialize a chemical reaction. These radicals are eliminated with the presence of oxygen and thus prevents the reaction. This suggests that the photoresist must be exposed to UV light for an extended time to completely remove oxygen for a chemical reaction to begin.
The research team, however, exploited the presence of oxygen. While the region affected by the UV light lowered oxygen concentration, the concentration in the untouched region remained unchanged. This difference in the concentrations caused a diffusion of oxygen to the region under UV light.
When the speed of the oxygen flow is slow, the diffusion occurs in parallel with the direction of the UV light. When fast, the diffusion process develops horizontally, outward from the area affected by the UV light. Professor Kim and his team proved this phenomenon both empirically and theoretically. Furthermore, by injecting an external oxygen source, the team was able to manipulate diffusion strength and direction, and thus control the shape and size of the polymer. The use of the polymerization inhibitors enabled and facilitated the fabrication of complex, three-dimensional micropatterns.
Professor Kim said, “While 3D printing is considered an innovative manufacturing technology, it cannot be used for mass-production of microscopic products. The new photolithographic technology will have a broad impact on both the academia and industry especially because existing, conventional photolithographic equipment can be used for the development of more complex micropatterns.” His newest technology will enhance the manufacturing process of three-dimensional polymers which were considered difficult to be commercialized.
The research was also dedicated to the late Professor Seung-Man Yang of the Department of Chemical and Biomolecular Engineering at KAIST. He was considered one of the greatest scholars in Korea in the field of hydrodynamics and colloids.
Picture 1: Featured Image of Nature Communications, March 2015
Picture 2: Polymers with various shapes and sizes produced with the new photolithographic technology developed by Professor Kim
2015.04.06 View 9725 -
Prof. Lee"s Team Succeeds in Producing Plastics Without Use of Fossil Fuels
A team of scientists led by Prof. Sang-Yup Lee of the Department of Biological Sciences at KAIST have succeeded in producing the polymers used for everyday plastics through bioengineering, rather than through the use of fossil fuel based chemicals, the university authorities said on Tuesday (Nov. 24).
This groundbreaking research, which may now allow for the production of environmentally conscious plastics, has been published in two papers in the journal Biotechnology and Bioengineering.
Polymers are molecules found in everyday life in the form of plastics and rubbers. The team consisted of scientists from KAIST and Korean chemical company LG Chem focused their research on polylactic acid (PLA), a bio-based polymer which holds the key to producing plastics through natural and renewable resources.
"The polyesters and other polymers we use everyday are mostly derived from fossil oils made through the refinery or chemical process," said Lee. "The idea of producing polymers from renewable biomass has attracted much attention due to the increasing concerns of environmental problems and the limited nature of fossil resources. PLA is considered a good alternative to petroleum based plastics as it is both biodegradable and has a low toxicity to humans."
Until now PLA has been produced in a two-step fermentation and chemical process of polymerization, which is both complex and expensive. Now, through the use of a metabolically engineered strain of E.coli, the team has developed a one-stage process which produces polylactic acid and its copolymers through direct fermentation. This makes the renewable production of PLA and lactate-containing copolymers cheaper and more commercially viable.
"By developing a strategy which combines metabolic engineering and enzyme engineering, we"ve developed an efficient bio-based one-step production process for PLA and its copolymers," said Lee. "This means that a developed E. coli strain is now capable of efficiently producing unnatural polymers, through a one-step fermentation process,"
This combined approach of systems-level metabolic engineering and enzyme engineering now allows for the production of polymer and polyester based products through direct microbial fermentation of renewable resources.
"Global warming and other environmental problems are urging us to develop sustainable processes based on renewable resources," concluded Lee. "This new strategy should be generally useful for developing other engineered organisms capable of producing various unnatural polymers by direct fermentation from renewable resources".
2009.11.30 View 13911