Advanced Materials - 2022 - Sabat  del R o - SEEDING to Enable Sensitive Electrochemical D
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Bridging the Gap between Nonliving Matter and Cellular Life

Sumit Kumar,Mamata Karmacharya,Yoon-Kyoung Cho*

Though synthetic micro or nanoreactors have been used to mimic life-like functions and to learn about the fundamental biology of natural cells, constructing a life-like structure out of non-living building blocks remains a considerable challenge. In this review, we focus on hybrid approaches that use both natural and synthetic materials to mimic and interface with biological systems. Using hybrid vesicle micro or nanoreactors, bioinspired life-like functions such as chemical compartments, cascade signaling, energy generation, growth, replication, and environmental adaptation are demonstrated. Here, we discuss the strategies for constructing cell membrane-engineered hybrid synthetic vesicles and their biomedical applications, as well as the remaining challenges and future research opportunities.

invited review

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[127] Lab Chip, 22, 2726-274, (2022)

Prediction of tumor metastasis via extracellular vesicles-treated platelet adhesion on a blood vessel chip

Junyoung Kim, Vijaya Sunkara, Jungmin Kim, Jooyoung Ro, Chi-Ju Kim, Elizabeth Maria Clarissa, Sung Wook Jung, Hee Jin Lee, and Yoon-Kyoung Cho*

Here, we found that interleukin-8 (IL-8) in cancer-derived EVs contributed to platelet activation by increasing P-selectin expression and ligand affinity, resulting in increased platelet adhesion on the human vessel-mimicking microfluidic system. Furthermore, platelet adhesion levels on vessels treated with human plasma-derived EVs demonstrated good discrimination between breast cancer patients with metastasis and those without, with the area under the curve (AUC) value of 0.88. While EpCAM expression on EVs could detect the existence of a tumor (AUC = 0.89), it performed poorly in predicting metastasis (AUC = 0.42). We believe that these findings shed light on the role of the interaction between cancer-derived EVs and platelets in pre-metastatic niche formation and tumor metastasis, potentially leading to the development of platelet–tumor interaction-based novel diagnostic and therapeutic strategies.

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[126] Advance Materials, 34, 2200981 (2022)

SEEDING to Enable Sensitive Electrochemical Detection of Biomarkers in Undiluted Biological Samples

Jonathan Sabaté del Río,Hyun-Kyung Woo,Juhee Park,Hong Koo Ha,Jae-Ryong Kim,Yoon-Kyoung Cho*

Electrochemical biosensors forf complex biological fluids such as plasma has been limited by the loss of sensitivity caused by biofouling. Herein, we demonstrate the preferential etching of chloride and surfactant-assisted anisotropic gold reduction to create homogeneous, nanostructured, and nanoporous gold electrodes, yielding 190 ± 20 times larger surface area within a minute without using templates. We named this process Surfactant-based Electrochemical Etch-Deposit Interplay for Nanostructure/Nanopore Growth (SEEDING). SEEDING on electrodes enhanced the sensitivity and anti-biofouling capabilities of amperometric biosensors, enabling direct analysis of tumor-derived extracellular vesicles (tEVs) in complex biofluids with a limit of detection of 300 tEVs/μL from undiluted plasma and good discrimination between patients with prostate cancer from healthy ones with an area under the curve (AUC) of 0.91 in urine and 0.90 in plasma samples.

Journal cover

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[125] Analyst, Analyst, 147, 2023-2034 (2022)

Recent advances in spheroid-based microfluidic models to mimic tumour microenvironment

Jooyoung Ro, Junyoung Kim, Yoon-Kyoung Cho

Three-dimensional (3D) multicellular spheroid models can recapitulate the human tumour microenvironment with more accuracy than conventional cell culture models, as they include complex architectural structures and dynamic cellular interactions. This review provides an overview of the advantages of 3D spheroid cultures with a summary of the recent applications for tumour microenvironment-focused cellular interactions, as well as the studies on spheroids and external stimuli. These 3D tumour spheroid-based microfluidic devices will provide a platform for a better understanding of cellular and external interactions, as well as the discovery of cancer therapeutics.

This article is part of the themed collections: Analyst Review Articles 2022 and Analyst HOT Articles 2022

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[124] Journal of Visualized Experiments : Jove. 2022 Feb(180). DOI: 10.3791/62836

Extracellular Vesicle Uptake Assay via Confocal Microscope Imaging Analysis

Chi-Ju Kim§*, Morgan D. Kuczler§, Liang Dong, Junyoung Kim, Sarah R. Amend, Yoon-Kyoung Cho*, Kenneth J. Pienta

EV uptake plays a role in intercellular communication in various research fields; cancer biology, neuroscience, and drug delivery. Fluorescently labeled EVs were prepared using a nano-filtration-based microfluidic device, Exodisc, visualized by 3D confocal microscopy, and then analyzed through advanced image-processing software. The protocol provides a robust methodology for analyzing EVs on a cellular level and a practical approach for efficient EV uptake analysis.

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[123] Translational Oncology, 16 (2022), 101321

Clinical Significance of Circulating Tumor Cells in Unresectable Pancreatic Ductal Adenocarcinomas

Hyemin Kim, Chan Mi Heo, Jinmyeong Oh, Eun Mi Lee, Juhee Park, Se-Hoon Lee, Kwang Hyuck Lee, Kyu Taek Lee, Jong Kyun Lee, Yoon-Kyoung Cho, Joo Kyung Park

Here, we investigated whether longitudinal analysis of CTCs could monitor disease progression, response to chemotherapy, and survival in patients with unresectable pancreatic ductal adenocarcinoma (PDAC).

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[122] Lab on a Chip, 22, 377-386 (2022)

Exhausted mature dendritic cells exhibit a slower and less persistent random motility but retain chemotaxis against CCL19

Yongjun Choi, Vijaya Sunkara, Yeojin Lee, and Yoon-Kyoung Cho*

The well-coordinated migration of DCs under various immunological or inflammatory conditions is
essential to ensure an effective immune response. Here, we studied the cellular migration of exhausted DCs in tissue-mimicked confined environments. We report a unique intrinsic cell migration behaviour of exhausted mature dendritic cells, which exhibit a slower, less persistent, and less diffusive random motility, which results in the DCs remaining at the site of infection, although a well preserved CCR7-dependent chemotactic motility is maintained.

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[121] Cells, 10(12), 3362 (2021)

Dendritic Cell Migration Is Tuned by Mechanical Stiffness of the Confining Space

Yongjun Choi, Jae-Eun Kwon, and Yoon-Kyoung Cho*

Dendritic cells (DCs), the sentinels of the immune system, are exposed to complex tissue microenvironments with a wide range of stiffnesses. Here, immature DCs were found to navigate confined spaces in a rapid and persistent manner, surveying a wide range when covered with compliant gels mimicking soft tissues. However, the speed and persistence time of random motility were both decreased by confinement in gels with higher stiffness, mimicking skin or diseased, fibrotic tissue. Our study provides evidence for a role for environmental mechanical stiffness in the surveillance strategy of immature DCs in tissues.

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[120] Lab on a Chip, 21, 4707-4715 (2021)

Fully automated light transmission aggregometry on a disc for platelet function tests

Chi-Ju Kim†, Jungmin Kim†, Jonathan Sabaté del Río, Dong Yeob Kia, Junyoung Kim, Yoon-Kyoung Cho*,

Platelet function tests, a group of assays that measure the ability of platelets to aggregate and promote clotting in a sample of blood, are performed in various medical fields to assess inherited platelet function disorders and monitor antiplatelet therapies. Here, we describe the design, fabrication, and operation of a centrifugal microfluidic disc that can perform a fully automated Light transmission aggregometry (LTA) assay from a small volume of a whole blood sample (<1 mL), achieving highly reproducible results (3.2% coefficient of variation) within a short period (<25 min). The assays performed with this device yield more precise and accurate results than traditional LTA because of the automation of the reaction steps, minimal human operation, and quick analysis that minimizes the adverse effects of platelet instability.

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[119]J. Clin. Med., 10(19), 4481 (2021)

Circulating Tumor Cells and TWIST Expression in Patients with Metastatic Gastric Cancer: A Preliminary Study

Joon Hyung Jhi, Gwang Ha Kim*, Su Jin Park, Dong Uk Kim, Moon Won Lee, Bong Eun Lee, Chae Hwa Kwon, and Yoon-Kyoung Cho,

The clinical significance of circulating tumor cells (CTCs) and TWIST expression in CTCs remains unelucidated in patients with gastric cancer (GC). Here, we evaluated CTCs and TWIST expression in CTCs and explored their correlation with prognosis in patients with metastatic GC. Our study demonstrated that high levels of CTCs and TWIST (+) CTCs were associated with worse OS.

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[118] Cancers 13, 21, 5272 (2021)

Circulating Tumor Cell Clusters Are Cloaked with Platelets and Correlate with Poor Prognosis in Unresectable Pancreatic Cancer

Minji Lim, Suhyun Park, Hyoung-Oh Jeong, Sung Hee Park, Sumit Kumar, Aelee Jang, Semin Lee, Dong Uk Kim*, Yoon-Kyoung Cho*

Despite recent advances, some patients with pancreatic cancer are refractory to treatment and the disease rapidly progresses, resulting in early death. The potential prognostic value of circulating tumor cells (CTCs) has been demonstrated in other cancer types, but the clinical validity in pancreatic cancer remains elusive. Here, we show that CTC clusters, which show mesenchymal characteristics and platelet marker expression, are highly correlated with poor prognosis in patients with unresectable pancreatic cancer.

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[117] Nature Catalysis, 4, 763-774 (2021)

Programmed exosome fusion for energy generation in living cells

Sumit Kumar, Mamata Karmacharya, Issac J. Michael, Yongjun Choi, Junyoung Kim, InUn Kim & Yoon-Kyoung Cho*

The design of artificial organelles for applications in living cells faces several challenges such as cellular uptake, stability and bio compatibility. Here, fusion of exosomes creates beneficial nanoreactors and their use for compartmentalized biocatalytic cascade reactions in cells is demonstrated. Exosome membrane proteins were chemically engineered with a catechol moiety to drive fusion by supramolecular complexation to bridge the membranes. This strategy successfully encapsulated multiple enzymes and assembled the minimal electron transport chain in the plasma membrane, leading to tuneable, enhanced catalytic cascade activity capable of ATP synthesis inside of tissue spheroids. This nanoreactor was functional for many hours after uptake into living cells, showed successful penetration into tissue spheroids and repaired the damaged region by supplying ATP, all of which represent an advance in the mimicking of nature’s own organelles.

journal cover

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[116] Acc. Chem. Res. 54, 19, 3643-3655 (2021)

Lab-on-a-Disc for Point-of-Care Infection Diagnostics

Vijaya Sunkara, Sumit Kumar, Jonathan Sabaté del Río, Insu Kim, and Yoon-Kyoung Cho*

Reliable, inexpensive, and rapid diagnostic tools are essential to control and prevent the spread of infectious diseases. In this Account, we detail the recent progress made by our group and others in the development of centrifugal microfluidic devices or lab-on-a-disc (LOAD) systems. Considering the urgent need for cost-effective and reliable POC infection diagnostic tools, especially in the current pandemic crisis, the current limitations and future directions of fast and broad adaptation in real-world settings are also discussed. With proper attention to key challenges and leverage with recent advances in biosensing technologies, molecular biology, nanomaterials, analytical chemistry, miniaturization, system integration, and data management, LOAD systems hold the potential to deliver POC infection diagnostic tools with unprecedented performance regarding time, accuracy, and cost. We hope the new insight and promise of LOAD systems for POC infection diagnostics presented in this Account can spark new ideas and inspire further research and development to create better healthcare systems for current and future pandemics.

invited review

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[115] Biosensors and Bioelectronics,194, 113584 (2021)

Lab-on-a-disc for ultrafast plasmonic assay of cysteamine

Mamata Karmacharya, Sumit Kumar, Chaeeun Lee, Yoon-Kyoung Cho*

Cysteamine (CA) is a cystine depleting agent used in the treatment of cystinosis and many other diseases. However, high dose of CA can be toxic and thus point-of-care-test devices measuring blood CA level can be highly beneficial. Here, we report a highly sensitive, straightforward, and quantitative assay for the colorimetric and spectroscopic determination of CA concentration using plasmonic nanoparticles. The principle is based on the chemical etching-induced exchange of the surface ligands of plasmonic gold nanoparticles (AuNPs) upon the addition of CA. This plasmonic AuNPs sensor displays a clear red-to-blue colorimetric transition in the presence of CA among various biothiols with high specificity and sensitivity within a short time (<15 s). This fully automated lab-on-a-disc platform approach for naked eye detecting the CA concentration in human blood samples (20 μL) is highly simple and time-efficient (<6 min), and it would be potentially useful for the careful selection of CA doses in the hospital industry.

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[114] Lab Chip, 21, 3263 - 3288 (2021)

The role of liquid biopsies in prostate cancer management

Chi-Ju Kim+, Liang Dong+, Sarah Amend*, Yoon-Kyoung Cho* and Kenneth Pienta*

The need to appropriately diagnose and guide the serial treatment of men with prostate cancer has led to the implementation of many studies to apply liquid biopsies to prostate cancer management. This review describes recent advancements in isolation and detection technology and the strength and weaknesses of the three circulating biomarkers. The clinical studies based on liquid biopsy results are summarized to depict the future perspective in the role of liquid biopsy on prostate cancer management.

This article is part of the themed collection: Microfluidics for hematology

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[113] ACS Appl. Nano Mater. 2021

Superhydrophobic and Self-Sterilizing Surgical Masks Spray-Coated with Carbon Nanotubes

Ritesh Soni, Shalik Ram Joshi, Mamata Karmacharya, Hyegi Min, Shin-Kwan Kim, Sumit Kumar*, Gun-Ho Kim*, Yoon-Kyoung Cho*, and Chang Young Lee*

Here, we report a single-step spray-coating technique for the formation of a superhydrophobic layer of single-walled carbon nanotubes (SWCNTs) on a melt-blown polypropylene (PP) surgical mask. Owing to the cumulative effect of the superhydrophobicity and photothermal performance of the SWCNTs, the CNT-coated masks show 99.99% higher bactericidal performance toward Escherichia coli than pristine masks. Further, the virucidal ability of the SWCNT-coated mask, tested by using virus-like particles, was found to be almost 99% under solar illumination. As the spray-coating method is easily scalable, the nanotube-coated mask provides cost-effective personal protection against respiratory diseases.

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[112] J. Am. Chem. Soc. 143, 28, 10582–10589 (2021)

Atomically Conformal Metal Laminations on Plasmonic Nanocrystals for Efficient Catalysis

Anubhab Acharya, Sateesh Dubbu, Sumit Kumar, Nitee Kumari, Yeseul Kim, Sunae So, Taewan Kwon, Zhipeng Wang, Junbeom Park, Yoon-Kyoung Cho, Junsuk Rho, Sang Ho Oh, Amit Kumar, In Su Lee

We introduce a “confine and shine” strategy to homogeneously modify the different surface curvatures of plasmonic NCs with ultrathin conformal layers of diverse catalytic noble metals. This self-limited epitaxial skinlike metal growth harvests the localized surface plasmon resonance to induce reduction chemistry directly on the NC surface, confined inside hollow silica. Unlike the conventional thick, anisotropic, and dendritic shells, which show severe nonradiative damping, the skinlike metal lamination preserves the key plasmonic properties of the core NCs. Consequently, the plasmonic–catalytic hybrid nanoreactors can carry out a variety of organic reactions with impressive rates.

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[111] ACS Appl. Mater. Interfaces 13, 25, 29313–29324 (2021)

Glycolipid-Anchored Proteins on Bioengineered Extracellular Vesicles for Lipopolysaccharide Neutralization

Divakara SSM Uppu, Yoohong Min, Inun Kim, Sumit Kumar, Juhee Park, and Yoon-Kyoung Cho*

This study reports bioengineered EVs with CD14, a natural glycosylphosphatidylinositol (GPI)-anchored protein and a selectively enriched native membrane protein on EVs. We demonstrated that producer cells transfected with genes encoding for GPI-anchored and transmembrane glycoproteins selectively display the former over the latter on bioengineered EVs. Natural GPI-anchored proteins are conserved receptors for bacterial toxins; for example, CD14 is an innate immune receptor for lipopolysaccharide (LPS), a gram-negative bacterial endotoxin. We reported that unlike soluble CD14, bioengineered EVs harboring CD14 reduce (50–90%) LPS-induced cytokine responses in mouse macrophages, including primary cells, possibly by reduced cell surface binding of LPS. These findings highlight the importance of harnessing the native EV membrane proteins, like GPI-anchored proteins, for functional studies such as toxin neutralization.

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[110] Frontiers in Bioengineering and Biotechnology, 2021, 9, 358

New Multiscale Characterization Methodology for Effective Determination of Isolation–Structure–Function Relationship of Extracellular Vesicles

Thanh Huyen Phan, Shiva Kamini Divakarla, Jia Hao Yeo, Qingyu Lei, Priyanka Tharkar, Taisa Nogueira Pansani, Kathryn G Leslie, Maggie Tong, Victoria A Coleman, Åsa Jämting, Mar-Dean Du Plessis, Elizabeth J New, Bill Kalionis, Philip Demokritou, Hyun-Kyung Woo, Yoon-Kyoung Cho, Wojciech Chrzanowski

Here, using a range of optical and non-optical techniques, we showed that the differences in molecular composition of EVs isolated using two isolation methods correlated with the differences in their biological function. Our results demonstrated that the isolation method determines the composition of isolated EVs at single and sub-population levels. Besides the composition, we measured for the first time the dry mass and predicted sedimentation of EVs. These parameters were likely to contribute to the biological and functional effects of EVs on single cell and cell cultures.

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[109] ACS Applied Materials & Interfaces, 13, 13, 15837–15846 (2021)

Spontaneous wrinkle formation on hydrogel surfaces using photoinitiator diffusion from oil-water interface

Eujin Um, Yoon-Kyoung Cho*, Joonwoo Jeong*

Patterning wrinkles on three-dimensional curved or enclosed surfaces can be challenging due to difficulties in application of uniform films and stresses on such structures. In this study, we demonstrate a simple one-step wrinkle-formation method on various hydrogel structures utilizing the oil-water interfaces. By diffusion of the photoinitiator from the oil phase to the prepolymer solution in water through the interface, a characteristic crosslinking gradient is set up in the hydrogel.