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Label-Free Multiplexed Microtomography of Endogenous Subcellular Dynamics Using Deep Learning
AI-based holographic microscopy allows molecular imaging without introducing exogenous labeling agents
A research team upgraded the 3D microtomography observing dynamics of label-free live cells in multiplexed fluorescence imaging. The AI-powered 3D holotomographic microscopy extracts various molecular information from live unlabeled biological cells in real time without exogenous labeling or staining agents.
Professor YongKeum Park’s team and the startup Tomocube encoded 3D refractive index tomograms using the refractive index as a means of measurement. Then they decoded the information with a deep learning-based model that infers multiple 3D fluorescence tomograms from the refractive index measurements of the corresponding subcellular targets, thereby achieving multiplexed micro tomography. This study was reported in Nature Cell Biology online on December 7, 2021.
Fluorescence microscopy is the most widely used optical microscopy technique due to its high biochemical specificity. However, it needs to genetically manipulate or to stain cells with fluorescent labels in order to express fluorescent proteins. These labeling processes inevitably affect the intrinsic physiology of cells. It also has challenges in long-term measuring due to photobleaching and phototoxicity. The overlapped spectra of multiplexed fluorescence signals also hinder the viewing of various structures at the same time. More critically, it took several hours to observe the cells after preparing them.
3D holographic microscopy, also known as holotomography, is providing new ways to quantitatively image live cells without pretreatments such as staining. Holotomography can accurately and quickly measure the morphological and structural information of cells, but only provides limited biochemical and molecular information.
The 'AI microscope' created in this process takes advantage of the features of both holographic microscopy and fluorescence microscopy. That is, a specific image from a fluorescence microscope can be obtained without a fluorescent label. Therefore, the microscope can observe many types of cellular structures in their natural state in 3D and at the same time as fast as one millisecond, and long-term measurements over several days are also possible.
The Tomocube-KAIST team showed that fluorescence images can be directly and precisely predicted from holotomographic images in various cells and conditions. Using the quantitative relationship between the spatial distribution of the refractive index found by AI and the major structures in cells, it was possible to decipher the spatial distribution of the refractive index. And surprisingly, it confirmed that this relationship is constant regardless of cell type.
Professor Park said, “We were able to develop a new concept microscope that combines the advantages of several microscopes with the multidisciplinary research of AI, optics, and biology. It will be immediately applicable for new types of cells not included in the existing data and is expected to be widely applicable for various biological and medical research.”
When comparing the molecular image information extracted by AI with the molecular image information physically obtained by fluorescence staining in 3D space, it showed a 97% or more conformity, which is a level that is difficult to distinguish with the naked eye.
“Compared to the sub-60% accuracy of the fluorescence information extracted from the model developed by the Google AI team, it showed significantly higher performance,” Professor Park added.
This work was supported by the KAIST Up program, the BK21+ program, Tomocube, the National Research Foundation of Korea, and the Ministry of Science and ICT, and the Ministry of Health & Welfare.
-Publication
Hyun-seok Min, Won-Do Heo, YongKeun Park, et al. “Label-free multiplexed microtomography of endogenous subcellular dynamics using generalizable deep learning,” Nature Cell Biology (doi.org/10.1038/s41556-021-00802-x) published online December 07 2021.
-Profile
Professor YongKeun Park
Biomedical Optics Laboratory
Department of Physics
KAIST
2022.02.09 View 8061 -
Eco-Friendly Micro-Supercapacitors Using Fallen Leaves
Green micro-supercapacitors on a single leaf could easily be applied in wearable electronics, smart houses, and IoTs
A KAIST research team has developed graphene-inorganic-hybrid micro-supercapacitors made of fallen leaves using femtosecond laser direct writing. The rapid development of wearable electronics requires breakthrough innovations in flexible energy storage devices in which micro-supercapacitors have drawn a great deal of interest due to their high power density, long lifetimes, and short charging times. Recently, there has been an enormous increase in waste batteries owing to the growing demand and the shortened replacement cycle in consumer electronics. The safety and environmental issues involved in the collection, recycling, and processing of such waste batteries are creating a number of challenges.
Forests cover about 30 percent of the Earth’s surface and produce a huge amount of fallen leaves. This naturally occurring biomass comes in large quantities and is completely biodegradable, which makes it an attractive sustainable resource. Nevertheless, if the fallen leaves are left neglected instead of being used efficiently, they can contribute to fire hazards, air pollution, and global warming.
To solve both problems at once, a research team led by Professor Young-Jin Kim from the Department of Mechanical Engineering and Dr. Hana Yoon from the Korea Institute of Energy Research developed a novel technology that can create 3D porous graphene microelectrodes with high electrical conductivity by irradiating femtosecond laser pulses on the leaves in ambient air. This one-step fabrication does not require any additional materials or pre-treatment.
They showed that this technique could quickly and easily produce porous graphene electrodes at a low price, and demonstrated potential applications by fabricating graphene micro-supercapacitors to power an LED and an electronic watch. These results open up a new possibility for the mass production of flexible and green graphene-based electronic devices.
Professor Young-Jin Kim said, “Leaves create forest biomass that comes in unmanageable quantities, so using them for next-generation energy storage devices makes it possible for us to reuse waste resources, thereby establishing a virtuous cycle.”
This research was published in Advanced Functional Materials last month and was sponsored by the Ministry of Agriculture Food and Rural Affairs, the Korea Forest Service, and the Korea Institute of Energy Research.
-Publication
Truong-Son Dinh Le, Yeong A. Lee, Han Ku Nam, Kyu Yeon Jang, Dongwook Yang, Byunggi Kim, Kanghoon Yim, Seung Woo Kim, Hana Yoon, and Young-jin Kim, “Green Flexible Graphene-Inorganic-Hybrid Micro-Supercapacitors Made of Fallen Leaves Enabled by Ultrafast Laser Pulses," December 05, 2021, Advanced Functional Materials (doi.org/10.1002/adfm.202107768)
-ProfileProfessor Young-Jin KimUltra-Precision Metrology and Manufacturing (UPM2) LaboratoryDepartment of Mechanical EngineeringKAIST
2022.01.27 View 9475 -
Nanoscale Self-Assembling Salt-Crystal ‘Origami’ Balls Envelop Liquids
Mechanical engineers have devised a ‘crystal capillary origami’ technique where salt crystals spontaneously encapsulate liquid droplets
Researchers have developed a technique whereby they can spontaneously encapsulate microscopic droplets of water and oil emulsion in a tiny sphere made of salt crystals—sort of like a minute, self-constructing origami soccer ball filled with liquid. The process, which they are calling ‘crystal capillary origami,’ could be used in a range of fields from more precise drug delivery to nanoscale medical devices.The technique is described in a paper appearing in the journal Nanoscale on September 21.
Capillary action, or ‘capillarity,’ will be familiar to most people as the way that water or other liquids can move up narrow tubes or other porous materials seemingly in defiance of gravity (for example within the vascular systems of plants, or even more simply, the drawing up of paint between the hairs of a paintbrush). This effect is due to the forces of cohesion (the tendency of a liquid’s molecules to stick together), which results in surface tension, and adhesion (their tendency to stick to the surface of other substances). The strength of the capillarity depends on the chemistry of the liquid, the chemistry of the porous material, and on the other forces acting on them both. For example, a liquid with lower surface tension than water would not be able to hold up a water strider insect.
Less well known is a related phenomenon, elasto-capillarity, that takes advantage of the relationship between capillarity and the elasticity of a very tiny flat sheet of a solid material. In certain circumstances, the capillary forces can overcome the elastic bending resistance of the sheet.
This relationship can be exploited to create ‘capillary origami,’ or three-dimensional structures. When a liquid droplet is placed on the flat sheet, the latter can spontaneously encapsulate the former due to surface tension. Capillary origami can take on other forms including wrinkling, buckling, or self-folding into other shapes. The specific geometrical shape that the 3D capillary origami structure ends up taking is determined by both the chemistry of the flat sheet and that of the liquid, and by carefully designing the shape and size of the sheet.
There is one big problem with these small devices, however. “These conventional self-assembled origami structures cannot be completely spherical and will always have discontinuous boundaries, or what you might call ‘edges,’ as a result of the original two-dimensional shape of the sheet,” said Kwangseok Park, a lead researcher on the project. He added, “These edges could turn out to be future defects with the potential for failure in the face of increased stress.” Non-spherical particles are also known to be more disadvantageous than spherical particles in terms of cellular uptake.
Professor Hyoungsoo Kim from the Department of Mechanical Engineering explained, “This is why researchers have long been on the hunt for substances that could produce a fully spherical capillary origami structure.”
The authors of the study have demonstrated such an origami sphere for the first time. They showed how instead of a flat sheet, the growth of salt-crystals can perform capillary origami action in a similar manner. What they call ‘crystal capillary origami’ spontaneously constructs a smooth spherical shell capsule from these same surface tension effects, but now the spontaneous encapsulation of a liquid is determined by the elasto-capillary conditions of growing crystals.
Here, the term ‘salt’ refers to a compound of one positively charged ion and another negatively charged. Table salt, or sodium chloride, is just one example of a salt. The researchers used four other salts: calcium propionate, sodium salicylate, calcium nitrate tetrahydrate, and sodium bicarbonate to envelop a water-oil emulsion. Normally, a salt such as sodium chloride has a cubical crystal structure, but these four salts form plate-like structures as crystallites or ‘grains’ (the microscopic shape that forms when a crystal first starts to grow) instead. These plates then self-assemble into perfect spheres.
Using scanning electron microscopy and X-ray diffraction analysis, they investigated the mechanism of such formation and concluded that it was ‘Laplace pressure’ that drives the crystallite plates to cover the emulsion surface. Laplace pressure describes the pressure difference between the interior and exterior of a curved surface caused by the surface tension at the interface between the two substances, in this case between the salt water and the oil.
The researchers hope that these self-assembling nanostructures can be used for encapsulation applications in a range of sectors, from the food industry and cosmetics to drug delivery and even tiny medical devices.
-Publication
Kwangseok Park, Hyoungsoo Kim “Crystal capillary origami capsule with self-assembled nanostructure,” Nanoscale, 13(35), 14656-14665 (DOI: 10.1039/d1nr02456f)
-Profile
Professor Hyoungsoo Kim
Fluid and Interface Laboratory
http://fil.kaist.ac.kr
Department of Mechanical Engineering
KAIST
2021.11.04 View 7393 -
New Chiral Nanostructures to Extend the Material Platform
Researchers observed a wide window of chiroptical activity from nanomaterials
A research team transferred chirality from the molecular scale to a microscale to extend material platforms and applications. The optical activity from this novel chiral material encompasses to short-wave infrared region.
This platform could serve as a powerful strategy for hierarchical chirality transfer through self-assembly, generating broad optical activity and providing immense applications including bio, telecommunication, and imaging technique. This is the first observation of such a wide window of chiroptical activity from nanomaterials.
“We synthesized chiral copper sulfides using cysteine, as the stabilizer, and transferring the chirality from molecular to the microscale through self-assembly,” explained Professor Jihyeon Yeom from the Department of Materials Science and Engineering, who led the research. The result was reported in ACS Nano on September 14.
Chiral nanomaterials provide a rich platform for versatile applications. Tuning the wavelength of polarization rotation maxima in the broad range is a promising candidate for infrared neural stimulation, imaging, and nanothermometry. However, the majority of previously developed chiral nanomaterials revealed the optical activity in a relatively shorter wavelength range, not in short-wave infrared.
To achieve chiroptical activity in the short-wave infrared region, materials should be in sub-micrometer dimensions, which are compatible with the wavelength of short-wave infrared region light for strong light-matter interaction. They also should have the optical property of short-wave infrared region absorption while forming a structure with chirality.
Professor Yeom’s team induced self-assembly of the chiral nanoparticles by controlling the attraction and repulsion forces between the building block nanoparticles. During this process, molecular chirality of cysteine was transferred to the nanoscale chirality of nanoparticles, and then transferred to the micrometer scale chirality of nanoflowers with 1.5-2 2 μm dimensions formed by the self-assembly.
“We will work to expand the wavelength range of chiroptical activity to the short-wave infrared region, thus reshaping our daily lives in the form of a bio-barcode that can store vast amount of information under the skin,” said Professor Yeom.
This study was funded by the Ministry of Science and ICT, the Ministry of Health and Welfare, the Ministry of Food and Drug Safety, the National Research Foundation of Korea,the KAIST URP Program, the KAIST Creative Challenging Research Program, Samsung and POSCO Science Fellowship.
-PublicationKi Hyun Park, Junyoung Kwon, Uichang Jeong, Ji-Young Kim, Nicholas A.Kotov, Jihyeon Yeom, “Broad Chrioptical Activity from Ultraviolet to Short-Wave Infrared by Chirality Transfer from Molecular to Micrometer Scale," September 14, 2021 ACS Nano (https://doi.org/10.1021/acsnano.1c05888)
-ProfileProfessor Jihyeon YeomNovel Nanomaterials for New Platforms LaboratoryDepartment of Materials Science and EngineeringKAIST
2021.10.22 View 7962 -
Flexible Sensor-Integrated RFA Needle Leads to Smarter Medical Treatment
Clinical trial of flexible sensor-integrated radiofrequency ablation (RFA) needle tip monitors physical changes and steam pop
Researchers have designed a thin polymeric sensor platform on a radiofrequency ablation needle to monitor temperature and pressure in real time. The sensors integrated onto 1.5 mm diameter needle tip have proven their efficacy during clinical tests and expect to provide a new opportunity for safer and more effective medical practices. The research was reported in Advanced Science as the frontispiece on August 5.
Radiofrequency ablation (RFA) is a minimally invasive surgery technique for removing tumors and treating cardiovascular disease. During a procedure, an unintended audible explosion called ‘steam pop’ can occur due to the increased internal steam pressure in the ablation region. This phenomenon has been cited as a cause of various negative thermal and mechanical effects on neighboring tissue. Even more, the relationship between steam pop and cancer recurrence is still being investigated.
Professor Inkyu Park said that his team’s integrated sensors reliably detected the occurrence of steam pop. The sensors also monitor rapidly spreading hot steam in tissue. It is expected that the diverse properties of tissue undergoing RFA could be checked by utilizing the physical sensors integrated on the needle.
“We believe that the integrated sensors can provide useful information about a variety of medical procedures and accompanying environmental changes in the human body, and help develop more effective and safer surgical procedures,” said Professor Park.
Professor Park’s team built a thin film type pressure and temperature sensor stack with a thickness of less than 10 μm using a microfabrication process. For the pressure sensor, the team used contact resistance changes between metal electrodes and a carbon nanotube coated polymeric membrane. The entire sensor array was thoroughly insulated with medical tubes to minimize any exposure of the sensor materials to external tissue and maximize its biocompatibility.
During the clinical trial, the research team found that the accumulated hot steam is suddenly released during steam pops and this hot air spreads to neighboring tissue, which accelerates the ablation process. Furthermore, using in-situ ultrasound imaging and computational simulations, the research team could confirm the non-uniform temperature distribution around the RFA needle can be one of the primary reasons for the steam popping.
Professor Park explained that various physical and chemical sensors for different targets can be added to create other medical devices and industrial tools.
“This result will expand the usability and applicability of current flexible sensor technologies. We are also trying to integrate this sensor onto a 0.3mm diameter needle for in-vivo diagnosis applications and expect that this approach can be applied to other medical treatments as well as the industrial field,” added Professor Park. This study was supported by the National Research Foundation of Korea.
-PublicationJaeho Park, Jinwoo Lee, Hyo Keun Lim, Inkyu Park et al. “Real-Time Internal Steam Pop Detection during Radiofrequency Ablation with a Radiofrequency Ablation Needle Integrated with a Temperature and Pressure Sensor: Preclinical and clinical pilot tests," Advanced Science (https://doi/org/10.1002/advs.202100725) on August 5, 2021
-ProfileProfessor Inkyu ParkMicro & Nano Tranducers Laboratory http://mintlab1.kaist.ac.kr/
Department of Mechanical EngineeringCollege of EngineeringKAIST
2021.10.20 View 6720 -
3D Visualization and Quantification of Bioplastic PHA in a Living Bacterial Cell
3D holographic microscopy leads to in-depth analysis of bacterial cells accumulating the bacterial bioplastic, polyhydroxyalkanoate (PHA)
A research team at KAIST has observed how bioplastic granule is being accumulated in living bacteria cells through 3D holographic microscopy. Their 3D imaging and quantitative analysis of the bioplastic ‘polyhydroxyalkanoate’ (PHA) via optical diffraction tomography provides insights into biosynthesizing sustainable substitutes for petroleum-based plastics.
The bio-degradable polyester polyhydroxyalkanoate (PHA) is being touted as an eco-friendly bioplastic to replace existing synthetic plastics. While carrying similar properties to general-purpose plastics such as polyethylene and polypropylene, PHA can be used in various industrial applications such as container packaging and disposable products.
PHA is synthesized by numerous bacteria as an energy and carbon storage material under unbalanced growth conditions in the presence of excess carbon sources. PHA exists in the form of insoluble granules in the cytoplasm. Previous studies on investigating in vivo PHA granules have been performed by using fluorescence microscopy, transmission electron microscopy (TEM), and electron cryotomography.
These techniques have generally relied on the statistical analysis of multiple 2D snapshots of fixed cells or the short-time monitoring of the cells. For the TEM analysis, cells need to be fixed and sectioned, and thus the investigation of living cells was not possible. Fluorescence-based techniques require fluorescence labeling or dye staining. Thus, indirect imaging with the use of reporter proteins cannot show the native state of PHAs or cells, and invasive exogenous dyes can affect the physiology and viability of the cells. Therefore, it was difficult to fully understand the formation of PHA granules in cells due to the technical limitations, and thus several mechanism models based on the observations have been only proposed.
The team of metabolic engineering researchers led by Distinguished Professor Sang Yup Lee and Physics Professor YongKeun Park, who established the startup Tomocube with his 3D holographic microscopy, reported the results of 3D quantitative label-free analysis of PHA granules in individual live bacterial cells by measuring the refractive index distributions using optical diffraction tomography. The formation and growth of PHA granules in the cells of Cupriavidus necator, the most-studied native PHA (specifically, poly(3-hydroxybutyrate), also known as PHB) producer, and recombinant Escherichia coli harboring C. necator PHB biosynthesis pathway were comparatively examined.
From the reconstructed 3D refractive index distribution of the cells, the team succeeded in the 3D visualization and quantitative analysis of cells and intracellular PHA granules at a single-cell level. In particular, the team newly presented the concept of “in vivo PHA granule density.” Through the statistical analysis of hundreds of single cells accumulating PHA granules, the distinctive differences of density and localization of PHA granules in the two micro-organisms were found. Furthermore, the team identified the key protein that plays a major role in making the difference that enabled the characteristics of PHA granules in the recombinant E. coli to become similar to those of C. necator.
The research team also presented 3D time-lapse movies showing the actual processes of PHA granule formation combined with cell growth and division. Movies showing the living cells synthesizing and accumulating PHA granules in their native state had never been reported before.
Professor Lee said, “This study provides insights into the morphological and physical characteristics of in vivo PHA as well as the unique mechanisms of PHA granule formation that undergo the phase transition from soluble monomers into the insoluble polymer, followed by granule formation. Through this study, a deeper understanding of PHA granule formation within the bacterial cells is now possible, which has great significance in that a convergence study of biology and physics was achieved. This study will help develop various bioplastics production processes in the future.”
This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (Grants NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557) and the Bio & Medical Technology Development Program (Grant No. 2021M3A9I4022740) from the Ministry of Science and ICT (MSIT) through the National Research Foundation (NRF) of Korea to S.Y.L. This work was also supported by the KAIST Cross-Generation Collaborative Laboratory project.
-PublicationSo Young Choi, Jeonghun Oh, JaeHwang Jung, YongKeun Park, and Sang Yup Lee. Three-dimensional label-free visualization and quantification of polyhydroxyalkanoates in individualbacterial cell in its native state. PNAS(https://doi.org./10.1073/pnas.2103956118)
-ProfileDistinguished Professor Sang Yup LeeMetabolic Engineering and Synthetic Biologyhttp://mbel.kaist.ac.kr/
Department of Chemical and Biomolecular Engineering KAIST
Endowed Chair Professor YongKeun ParkBiomedical Optics Laboratoryhttps://bmokaist.wordpress.com/
Department of PhysicsKAIST
2021.07.28 View 10252 -
VP Sang Yup Lee Honored with the Pony Chung Innovation Award
Vice President for Research Sang Yup Lee became the recipient of the Innovation Award by the Pony Chung Foundation that was established to honor the late Se-yung Chung, the former chairman of Hyundai Development Company. He will receive 200 million KRW in prize money. Chairman Chung developed Korea’s first domestically manufactured automobile, ‘Pony,’ in the mid-1970s that became the cornerstone of Korea’s auto industry today.
Distinguished Professor Lee, from the Department of Chemical and Biomolecular Engineering, is a pioneering scholar in the field of systems metabolic engineering who developed various micro-organisms for producing a wide range of fuels, chemicals, materials, and natural compounds.
He recently was elected as a foreign member of the Royal Society in the UK and is the first Korean ever elected into the National Academy of Inventors (NAI) in the US as well as one of 13 scholars elected as an International Member of both the National Academy of Sciences (NAS) and the National Academy of Engineering (NAE) in the US.
2021.07.13 View 7579 -
Quantum Laser Turns Energy Loss into Gain
A new laser that generates quantum particles can recycle lost energy for highly efficient, low threshold laser applications
Scientists at KAIST have fabricated a laser system that generates highly interactive quantum particles at room temperature. Their findings, published in the journal Nature Photonics, could lead to a single microcavity laser system that requires lower threshold energy as its energy loss increases.
The system, developed by KAIST physicist Yong-Hoon Cho and colleagues, involves shining light through a single hexagonal-shaped microcavity treated with a loss-modulated silicon nitride substrate. The system design leads to the generation of a polariton laser at room temperature, which is exciting because this usually requires cryogenic temperatures.
The researchers found another unique and counter-intuitive feature of this design. Normally, energy is lost during laser operation. But in this system, as energy loss increased, the amount of energy needed to induce lasing decreased. Exploiting this phenomenon could lead to the development of high efficiency, low threshold lasers for future quantum optical devices.
“This system applies a concept of quantum physics known as parity-time reversal symmetry,” explains Professor Cho. “This is an important platform that allows energy loss to be used as gain. It can be used to reduce laser threshold energy for classical optical devices and sensors, as well as quantum devices and controlling the direction of light.”
The key is the design and materials. The hexagonal microcavity divides light particles into two different modes: one that passes through the upward-facing triangle of the hexagon and another that passes through its downward-facing triangle. Both modes of light particles have the same energy and path but don’t interact with each other.
However, the light particles do interact with other particles called excitons, provided by the hexagonal microcavity, which is made of semiconductors. This interaction leads to the generation of new quantum particles called polaritons that then interact with each other to generate the polariton laser. By controlling the degree of loss between the microcavity and the semiconductor substrate, an intriguing phenomenon arises, with the threshold energy becoming smaller as energy loss increases. This research was supported by the Samsung Science and Technology Foundation and Korea’s National Research Foundation.
-PublicationSong,H.G, Choi, M, Woo, K.Y. Yong-Hoon Cho Room-temperature polaritonic non-Hermitian system with single microcavityNature Photonics (https://doi.org/10.1038/s41566-021-00820-z)
-ProfileProfessor Yong-Hoon ChoQuantum & Nanobio Photonics Laboratoryhttp://qnp.kaist.ac.kr/
Department of PhysicsKAIST
2021.07.07 View 8333 -
Wearable Device to Monitor Sweat in Real Time
An on-skin platform for the wireless monitoring of flow rate, cumulative loss, and temperature of sweat in real time
An electronic patch can monitor your sweating and check your health status. Even more, the soft microfluidic device that adheres to the surface of the skin, captures, stores, and performs biomarker analysis of sweat as it is released through the eccrine glands.
This wearable and wireless electronic device developed by Professor Kyeongha Kwon and her collaborators is a digital and wireless platform that could help track the so-called ‘filling process’ of sweat without having to visually examine the device. The platform was integrated with microfluidic systems to analyze the sweat’s components.
To monitor the sweat release rate in real time, the researchers created a ‘thermal flow sensing module.’ They designed a sophisticated microfluidic channel to allow the collected sweat to flow through a narrow passage and a heat source was placed on the outer surface of the channel to induce a heat exchange between the sweat and the heated channel.
As a result, the researchers could develop a wireless electronic patch that can measure the temperature difference in a specific location upstream and downstream of the heat source with an electronic circuit and convert it into a digital signal to measure the sweat release rate in real time. The patch accurately measured the perspiration rate in the range of 0-5 microliters/minute (μl/min), which was considered physiologically significant. The sensor can measure the flow of sweat directly and then use the information it collected to quantify total sweat loss. Moreover, the device features advanced microfluidic systems and colorimetric chemical reagents to gather pH measurements and determine the concentration of chloride, creatinine, and glucose in a user's sweat.
Professor Kwon said that these indicators could be used to diagnose various diseases related with sweating such as cystic fibrosis, diabetes, kidney dysfunction, and metabolic alkalosis. “As the sweat flowing in the microfluidic channel is completely separated from the electronic circuit, the new patch overcame the shortcomings of existing flow rate measuring devices, which were vulnerable to corrosion and aging,” she explained.
The patch can be easily attached to the skin with flexible circuit board printing technology and silicone sealing technology. It has an additional sensor that detects changes in skin temperature. Using a smartphone app, a user can check the data measured by the wearable patch in real time.
Professor Kwon added, “This patch can be widely used for personal hydration strategies, the detection of dehydration symptoms, and other health management purposes. It can also be used in a systematic drug delivery system, such as for measuring the blood flow rate in blood vessels near the skin’s surface or measuring a drug’s release rate in real time to calculate the exact dosage.”
-PublicationKyeongha Kwon, Jong Uk Kim, John A. Rogers, et al. “An on-skin platform for wireless monitoring of flow rate, cumulative loss and temperature of sweat in real time.” Nature Electronics (doi.org/10.1038/s41928-021-00556-2)
-ProfileProfessor Kyeongha KwonSchool of Electrical EngineeringKAIST
2021.06.25 View 8035 -
Natural Rainbow Colorants Microbially Produced
Integrated strategies of systems metabolic engineering and membrane engineering led to the production of natural rainbow colorants comprising seven natural colorants from bacteria for the first time
A research group at KAIST has engineered bacterial strains capable of producing three carotenoids and four violacein derivatives, completing the seven colors in the rainbow spectrum. The research team integrated systems metabolic engineering and membrane engineering strategies for the production of seven natural rainbow colorants in engineered Escherichia coli strains. The strategies will be also useful for the efficient production of other industrially important natural products used in the food, pharmaceutical, and cosmetic industries.
Colorants are widely used in our lives and are directly related to human health when we eat food additives and wear cosmetics. However, most of these colorants are made from petroleum, causing unexpected side effects and health problems. Furthermore, they raise environmental concerns such as water pollution from dyeing fabric in the textiles industry. For these reasons, the demand for the production of natural colorants using microorganisms has increased, but could not be readily realized due to the high cost and low yield of the bioprocesses.
These challenges inspired the metabolic engineers at KAIST including researchers Dr. Dongsoo Yang and Dr. Seon Young Park, and Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering. The team reported the study entitled “Production of rainbow colorants by metabolically engineered Escherichia coli” in Advanced Science online on May 5. It was selected as the journal cover of the July 7 issue.
This research reports for the first time the production of rainbow colorants comprising three carotenoids and four violacein derivatives from glucose or glycerol via systems metabolic engineering and membrane engineering. The research group focused on the production of hydrophobic natural colorants useful for lipophilic food and dyeing garments. First, using systems metabolic engineering, which is an integrated technology to engineer the metabolism of a microorganism, three carotenoids comprising astaxanthin (red), -carotene (orange), and zeaxanthin (yellow), and four violacein derivatives comprising proviolacein (green), prodeoxyviolacein (blue), violacein (navy), and deoxyviolacein (purple) could be produced. Thus, the production of natural colorants covering the complete rainbow spectrum was achieved.
When hydrophobic colorants are produced from microorganisms, the colorants are accumulated inside the cell. As the accumulation capacity is limited, the hydrophobic colorants could not be produced with concentrations higher than the limit. In this regard, the researchers engineered the cell morphology and generated inner-membrane vesicles (spherical membranous structures) to increase the intracellular capacity for accumulating the natural colorants. To further promote production, the researchers generated outer-membrane vesicles to secrete the natural colorants, thus succeeding in efficiently producing all of seven rainbow colorants. It was even more impressive that the production of natural green and navy colorants was achieved for the first time.
“The production of the seven natural rainbow colorants that can replace the current petroleum-based synthetic colorants was achieved for the first time,” said Dr. Dongsoo Yang. He explained that another important point of the research is that integrated metabolic engineering strategies developed from this study can be generally applicable for the efficient production of other natural products useful as pharmaceuticals or nutraceuticals. “As maintaining good health in an aging society is becoming increasingly important, we expect that the technology and strategies developed here will play pivotal roles in producing other valuable natural products of medical or nutritional importance,” explained Distinguished Professor Lee.
This work was supported by the "Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ01550602)" Rural Development Administration, Republic of Korea.
-Publication:Dongsoo Yang, Seon Young Park, and Sang Yup Lee. Production of rainbow colorants by metabolically engineered Escherichia coli. Advanced Science, 2100743.
-Profile Distinguished Professor Sang Yup LeeMetabolic &Biomolecular Engineering National Research Laboratoryhttp://mbel.kaist.ac.kr
Department of Chemical and Biomolecular EngineeringKAIST
2021.06.09 View 8764 -
Distinguished Professor Sang Yup Lee Honored with Charles D. Scott Award
Vice President for Research Sang Yup Lee received the 2021 Charles D. Scott Award from the Society for Industrial Microbiology and Biotechnology. Distinguished Professor Lee from the Department of Chemical and Biomolecular Engineering at KAIST is the first Asian awardee.
The Charles D. Scott Award, initiated in 1995, recognizes individuals who have made significant contributions to enable and further the use of biotechnology to produce fuels and chemicals. The award is named in honor of Dr. Charles D. Scott, who founded the Symposium on Biomaterials, Fuels, and Chemicals and chaired the conference for its first ten years.
Professor Lee has pioneered systems metabolic engineering and developed various micro-organisms capable of producing a wide range of fuels, chemicals, materials, and natural compounds, many of them for the first time. Some of the breakthroughs include the microbial production of gasoline, diacids, diamines, PLA and PLGA polymers, and several natural products.
More recently, his team has developed a microbial strain capable of the mass production of succinic acid, a monomer for manufacturing polyester, with the highest production efficiency to date, as well as a Corynebacterium glutamicum strain capable of producing high-level glutaric acid. They also engineered for the first time a bacterium capable of producing carminic acid, a natural red colorant that is widely used for food and cosmetics.
Professor Lee is one of the Highly Cited Researchers (HCR), ranked in the top 1% by citations in their field by Clarivate Analytics for four consecutive years from 2017. He is the first Korean fellow ever elected into the National Academy of Inventors in the US and one of 13 scholars elected as an International Member of both the National Academy of Sciences and the National Academy of Engineering in the USA.
The awards ceremony will take place during the Symposium on Biomaterials, Fuels, and Chemicals held online from April 26.
2021.04.27 View 7833 -
Microbial Production of a Natural Red Colorant Carminic Acid
Metabolic engineering and computer-simulated enzyme engineering led to the production of carminic acid, a natural red colorant, from bacteria for the first time
A research group at KAIST has engineered a bacterium capable of producing a natural red colorant, carminic acid, which is widely used for food and cosmetics. The research team reported the complete biosynthesis of carminic acid from glucose in engineered Escherichia coli. The strategies will be useful for the design and construction of biosynthetic pathways involving unknown enzymes and consequently the production of diverse industrially important natural products for the food, pharmaceutical, and cosmetic industries.
Carminic acid is a natural red colorant widely being used for products such as strawberry milk and lipstick. However, carminic acid has been produced by farming cochineals, a scale insect which only grows in the region around Peru and Canary Islands, followed by complicated multi-step purification processes. Moreover, carminic acid often contains protein contaminants that cause allergies so many people are unwilling to consume products made of insect-driven colorants. On that account, manufacturers around the world are using alternative red colorants despite the fact that carminic acid is one of the most stable natural red colorants.
These challenges inspired the metabolic engineering research group at KAIST to address this issue. Its members include postdoctoral researchers Dongsoo Yang and Woo Dae Jang, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering. This study entitled “Production of carminic acid by metabolically engineered Escherichia coli” was published online in the Journal of the American Chemical Society (JACS) on April 2.
This research reports for the first time the development of a bacterial strain capable of producing carminic acid from glucose via metabolic engineering and computer simulation-assisted enzyme engineering. The research group optimized the type II polyketide synthase machinery to efficiently produce the precursor of carminic acid, flavokermesic acid.
Since the enzymes responsible for the remaining two reactions were neither discovered nor functional, biochemical reaction analysis was performed to identify enzymes that can convert flavokermesic acid into carminic acid. Then, homology modeling and docking simulations were performed to enhance the activities of the two identified enzymes. The team could confirm that the final engineered strain could produce carminic acid directly from glucose. The C-glucosyltransferase developed in this study was found to be generally applicable for other natural products as showcased by the successful production of an additional product, aloesin, which is found in aloe leaves.
“The most important part of this research is that unknown enzymes for the production of target natural products were identified and improved by biochemical reaction analyses and computer simulation-assisted enzyme engineering,” says Dr. Dongsoo Yang. He explained the development of a generally applicable C-glucosyltransferase is also useful since C-glucosylation is a relatively unexplored reaction in bacteria including Escherichia coli. Using the C-glucosyltransferase developed in this study, both carminic acid and aloesin were successfully produced from glucose.
“A sustainable and insect-free method of producing carminic acid was achieved for the first time in this study. Unknown or inefficient enzymes have always been a major problem in natural product biosynthesis, and here we suggest one effective solution for solving this problem. As maintaining good health in the aging society is becoming increasingly important, we expect that the technology and strategies developed here will play pivotal roles in producing other valuable natural products of medical or nutritional importance,” said Distinguished Professor Sang Yup Lee.
This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries of the Ministry of Science and ICT (MSIT) through the National Research Foundation (NRF) of Korea and the KAIST Cross-Generation Collaborative Lab project; Sang Yup Lee and Dongsoo Yang were also supported by Novo Nordisk Foundation in Denmark.
Publication:
Dongsoo Yang, Woo Dae Jang, and Sang Yup Lee. Production of carminic acid by metabolically engineered Escherichia coli. at the Journal of the American Chemical Society. https://doi.org.10.1021/jacs.0c12406
Profile:
Sang Yup Lee, PhD
Distinguished Professor
leesy@kaist.ac.kr
http://mbel.kaist.ac.kr
Metabolic &Biomolecular Engineering National Research Laboratory
Department of Chemical and Biomolecular Engineering
KAIST
2021.04.06 View 10267