Publications by authors named "Jungil Choi"

67 Publications

Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells.

Redox Biol 2021 Sep 21;47:102144. Epub 2021 Sep 21.

Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.
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http://dx.doi.org/10.1016/j.redox.2021.102144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476449PMC
September 2021

Color-Coded Droplets and Microscopic Image Analysis for Multiplexed Antibiotic Susceptibility Testing.

Biosensors (Basel) 2021 Aug 19;11(8). Epub 2021 Aug 19.

School of Mechanical Engineering, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul 02707, Korea.

Since the discovery of antibiotics, the emergence of antibiotic resistance has become a global issue that is threatening society. In the era of antibiotic resistance, finding the proper antibiotics through antibiotic susceptibility testing (AST) is crucial in clinical settings. However, the current clinical process of AST based on the broth microdilution test has limitations on scalability to expand the number of antibiotics that are tested with various concentrations. Here, we used color-coded droplets to expand the multiplexing of AST regarding the kind and concentration of antibiotics. Color type and density differentiate the kind of antibiotics and concentration, respectively. Microscopic images of a large view field contain numbers of droplets with different testing conditions. Image processing analysis detects each droplet, decodes color codes, and measures the bacterial growth in the droplet. Testing ATCC 25922 with ampicillin, gentamicin, and tetracycline shows that the system can provide a robust and scalable platform for multiplexed AST. Furthermore, the system can be applied to various drug testing systems, which require several different testing conditions.
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http://dx.doi.org/10.3390/bios11080283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393621PMC
August 2021

Battery-free, wireless soft sensors for continuous multi-site measurements of pressure and temperature from patients at risk for pressure injuries.

Nat Commun 2021 08 24;12(1):5008. Epub 2021 Aug 24.

Department of Electrical and Computer Engineering, Sungkyunkwan University, Suwon, Republic of Korea.

Capabilities for continuous monitoring of pressures and temperatures at critical skin interfaces can help to guide care strategies that minimize the potential for pressure injuries in hospitalized patients or in individuals confined to the bed. This paper introduces a soft, skin-mountable class of sensor system for this purpose. The design includes a pressure-responsive element based on membrane deflection and a battery-free, wireless mode of operation capable of multi-site measurements at strategic locations across the body. Such devices yield continuous, simultaneous readings of pressure and temperature in a sequential readout scheme from a pair of primary antennas mounted under the bedding and connected to a wireless reader and a multiplexer located at the bedside. Experimental evaluation of the sensor and the complete system includes benchtop measurements and numerical simulations of the key features. Clinical trials involving two hemiplegic patients and a tetraplegic patient demonstrate the feasibility, functionality and long-term stability of this technology in operating hospital settings.
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http://dx.doi.org/10.1038/s41467-021-25324-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385057PMC
August 2021

Microscopic Analysis of Bacterial Inoculum Effect Using Micropatterned Biochip.

Antibiotics (Basel) 2021 Mar 13;10(3). Epub 2021 Mar 13.

School of Mechanical Engineering, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul 02707, Korea.

Antimicrobial resistance has become a major problem in public health and clinical environments. Against this background, antibiotic susceptibility testing (AST) has become necessary to cure diseases in an appropriate and timely manner as it indicates the necessary concentration of antibiotics. Recently, microfluidic based rapid AST methods using microscopic analysis have been shown to reduce the time needed for the determination of the proper antibiotics. However, owing to the inoculum effect, the accurate measurement of the minimal inhibitory concentration (MIC) is difficult. We tested four standard bacteria: , against five different antibiotics: piperacillin, cefotaxime, amikacin, levofloxacin, and ampicillin. The results showed that overall, the microfluidic system has a similar inoculum effect compared to the conventional AST method. However, due to the different testing conditions and determination protocols of the growth of the microfluidic based rapid AST, a few results are not identical to the conventional methods using optical density. This result suggests that microfluidic based rapid AST methods require further research on the inoculum effect for practical use in hospitals and can then be used for effective antibiotic prescriptions.
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http://dx.doi.org/10.3390/antibiotics10030300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998646PMC
March 2021

Soft, skin-interfaced sweat stickers for cystic fibrosis diagnosis and management.

Sci Transl Med 2021 03;13(587)

Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL 60202, USA.

The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") designed for the simple and rapid collection and analysis of sweat. Intimate, conformal coupling with the skin supports nearly perfect efficiency in sweat collection without leakage. Real-time image analysis of chloride reagents allows for quantitative assessment of chloride concentrations using a smartphone camera, without requiring extraction of sweat or external analysis. Clinical validation studies involving patients with CF and healthy subjects, across a spectrum of age groups, support clinical equivalence compared to existing device platforms in terms of accuracy and demonstrate meaningful reductions in rates of leakage. The wearable microfluidic technologies and smartphone-based analytics reported here establish the foundation for diagnosis of CF outside of clinical settings.
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http://dx.doi.org/10.1126/scitranslmed.abd8109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351625PMC
March 2021

Visualization of superficial vein dynamics in dorsal hand by near-infrared imaging in response to elevated local temperature.

J Biomed Opt 2021 02;26(2)

Kookmin Univ., Korea, Republic of.

Significance: Dry or moist skin-contact thermal stimulation for vein puncture (VP) and vein cannulation (VC) may not be feasible for sensitive skin. For a damaged, burned, or dark skin, near-infrared (NIR) imaging is preferred to visualize a vein. Postprocessing of NIR images is always required because the skin is a reflective material and veins need segmentation for quantitative analysis.

Aim: Our pilot study aims to observe the effect of noncontact local heating on the superficial metacarpal veins in the dorsal surface of the hand and to visualize vein dynamics using an NIR imaging system.

Approach: Our experiment consists of studies A and B at two ambient temperatures, 19°C and 25°C. A simple reflection-based NIR imaging system was installed to acquire sequential vein images for 5 min before and after applying 10 min of radiant thermal stimulation. To measure the vein diameter (VD), we trained a convolutional neural network (CNN) on sequential raw images to predict vein-segmentation masks as output images. Later these masked images were postprocessed for the VD measurements.

Results: The average VD was significantly increased after thermal stimulation in study A. The maximum increments in VD were 39.3% and 9.19%, 1 min after thermal stimulation in studies A and B, respectively. Both the VD and skin temperature (Tskin) follow negative exponentials in time, and the VD is proportional to Tskin. A multiple linear-regression model was made to predict the final VD. A significant difference was observed in the change of the VD.

Conclusions: NIR imaging with CNN can be used for quantitative analyses of vein dynamics. This finding can be further extended to develop real-time, image-guided medical devices by integrating them with a radiant heater and to assist medical practitioners in achieving high success rates for VP or VC.
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http://dx.doi.org/10.1117/1.JBO.26.2.026003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900829PMC
February 2021

Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer.

Pharmaceuticals (Basel) 2021 Jan 6;14(1). Epub 2021 Jan 6.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju-si 52828, Korea.

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.
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http://dx.doi.org/10.3390/ph14010038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825493PMC
January 2021

A high-throughput cell culture system based on capillary and centrifugal actions for rapid antimicrobial susceptibility testing.

Lab Chip 2020 12;20(24):4552-4560

QuantaMatrix Inc., Seoul National University Hospital CMI, Seoul, 03082, Republic of Korea and Department of Electrical Engineering and Computer Science, Seoul National University, Seoul, 08826, Republic of Korea.

Antibiotic resistance is a global threat to modern society. Rapid determination of suitable antibiotics that inhibit bacterial growth can effectively reduce antibiotic resistance and improve clinical treatment. The conventional methods of antimicrobial susceptibility testing (AST) depend on optical density measurements, which require long-time incubation. Various kinds of rapid AST systems which utilize various technologies from the field of lab on a chip have promised a great reduction in measurement time, but cannot achieve high-throughput, user-friendly testing due to the complexity of the testing system. Here, we introduce a capillary and centrifuge-based rapid AST system that reduces the time of loading the sample and culture media while achieving a high-throughput testing capacity. The capability of the proposed system is validated in a systematic analysis that includes sample loading characteristics and AST trials with standard strains. The proposed system provides a useful tool for drug testing in cell-culture systems with user-friendly and high-throughput analysis.
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http://dx.doi.org/10.1039/d0lc00753fDOI Listing
December 2020

Skin-interfaced soft microfluidic systems with modular and reusable electronics for capacitive sensing of sweat loss, rate and conductivity.

Lab Chip 2020 11;20(23):4391-4403

Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL 60208, USA.

Important insights into human health can be obtained through the non-invasive collection and detailed analysis of sweat, a biofluid that contains a wide range of essential biomarkers. Skin-interfaced microfluidic platforms, characterized by soft materials and thin geometries, offer a collection of capabilities for in situ capture, storage, and analysis of sweat and its constituents. In ambulatory uses cases, the ability to provide real-time feedback on sweat loss, rate and content, without visual inspection of the device, can be important. This paper introduces a low-profile skin-interfaced system that couples disposable microfluidic sampling devices with reusable 'stick-on' electrodes and wireless readout electronics that remain isolated from the sweat. An ultra-thin capping layer on the microfluidic platform permits high-sensitivity, contactless capacitive measurements of both sweat loss and sweat conductivity. This architecture avoids the potential for corrosion of the sensing components and eliminates the need for cleaning/sterilizing the electronics, thereby resulting in a cost-effective platform that is simple to use. Optimized electrode designs follow from a combination of extensive benchtop testing, analytical calculations and FEA simulations for two sensing configurations: (1) sweat rate and loss, and (2) sweat conductivity, which contains information about electrolyte content. Both configurations couple to a flexible, wireless electronics platform that digitizes and transmits information to Bluetooth-enabled devices. On-body field testing during physical exercise validates the performance of the system in scenarios of practical relevance to human health and performance.
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http://dx.doi.org/10.1039/d0lc00705fDOI Listing
November 2020

Skin-Interfaced Microfluidic Systems that Combine Hard and Soft Materials for Demanding Applications in Sweat Capture and Analysis.

Adv Healthc Mater 2021 02 29;10(4):e2000722. Epub 2020 Sep 29.

Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA.

Eccrine sweat contains a rich blend of electrolytes, metabolites, proteins, metal ions, and other biomarkers. Changes in the concentrations of these chemical species can indicate alterations in hydration status and they can also reflect health conditions such as cystic fibrosis, schizophrenia, and depression. Recent advances in soft, skin-interfaced microfluidic systems enable real-time measurement of local sweat loss and sweat biomarker concentrations, with a wide range of applications in healthcare. Uses in certain contexts involve, however, physical impacts on the body that can dynamically deform these platforms, with adverse effects on measurement reliability. The work presented here overcomes this limitation through the use of microfluidic structures constructed in relatively high modulus polymers, and designed in geometries that offer soft, system level mechanics when embedded low modulus elastomers. Analytical models and finite element analysis quantitatively define the relevant mechanics of these systems, and serve as the basis for layouts optimized to allow robust operation in demanding, rugged scenarios such as those encountered in football, while preserving mechanical stretchability for comfortable, water-tight bonding to the skin. Benchtop testing and on-body field studies of measurements of sweat loss and chloride concentration under imposed mechanical stresses and impacts demonstrate the key features of these platforms.
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http://dx.doi.org/10.1002/adhm.202000722DOI Listing
February 2021

Post-Antibiotic Effect of Ampicillin and Levofloxacin to and Based on Microscopic Imaging Analysis.

Antibiotics (Basel) 2020 Jul 29;9(8). Epub 2020 Jul 29.

School of Mechanical Engineering, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul 02707, Korea.

Post-antibiotic effect (PAE) is the continued suppression of bacterial growth following a limited exposure to an antimicrobial agent. The presence of PAE needs consequential consideration in designing antibiotic dosage regimens. To understand the behavior of bacteria, PAE provides information on how long antibiotics are applied to the bacteria. Conventional methods of measuring PAE depend on population detection and have limitations for understanding the individual behavior of bacteria. To observe the PAE, we utilized an imaging technique with the use of microscopy. Here, we discuss the microscopic image analysis system we used to study the PAE at a single-colony level. The size and number of colonies of bacteria were measured prior to and following antibiotic removal. We could count a single colony, see the development of the settlement prior to and following exposure of antibiotics and track the colony by microscopy according to the incubation time and the image processed by our own image processing program. The PAE of antibiotics was quantified by comparing bacteria size and number based on their exposure time. In our study, we discovered that the longer exposure of antibiotics causes the bacteria to be suppressed-even after washing the antibiotics from the solution. This finding suggests that microscopic imaging detection provides a new method for understanding PAE. In addition, the behavior of the cell in response to drugs and chemicals and their removal can be examined with the use of single colony analysis.
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http://dx.doi.org/10.3390/antibiotics9080458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459589PMC
July 2020

Rapid Capture and Extraction of Sweat for Regional Rate and Cytokine Composition Analysis Using a Wearable Soft Microfluidic System.

J Invest Dermatol 2021 02 17;141(2):433-437.e3. Epub 2020 Jun 17.

Epicore Biosystems, Cambridge, Massachusetts, USA; Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, Illinois, USA; Center for Bio-Integrated Electronics, Northwestern University, Evanston, Illinois, USA; Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA; Institute for Innovations in Development Science, Northwestern University, Evanston, Illinois, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.05.107DOI Listing
February 2021

Discovery of orally active indirubin-3'-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia.

Eur J Med Chem 2020 Jun 6;195:112205. Epub 2020 Mar 6.

Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea; School of Life Sciences and Center for AI-applied High Efficiency Drug Discovery, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. Electronic address:

FMS-like receptor tyrosine kinase-3 (FLT3) is expressed on acute leukemia cells and is implicated in the survival, proliferation and differentiation of hematopoietic cells in most acute myeloid leukemia (AML) patients. Despite recent achievements in the development of FLT3-targeted small-molecule drugs, there are still unmet medical needs related to kinase selectivity and the progression of some mutant forms of FLT3. Herein, we describe the discovery of novel orally available type 1 FLT3 inhibitors from structure-activity relationship (SAR) studies for the optimization of indirubin derivatives with biological and pharmacokinetic profiles as potential therapeutic agents for AML. The SAR exploration provided important structural insights into the key substituents for potent inhibitory activities of FLT3 and in MV4-11 cells. The profile of the most optimized inhibitor (36) showed IC values of 0.87 and 0.32 nM against FLT3 and FLT3/D835Y, respectively, along with potent inhibition against MV4-11 and FLT3/D835Y expressed MOLM14 cells with a GI value of 1.0 and 1.87 nM, respectively. With the high oral bioavailability of 42.6%, compound 36 displayed significant in vivo antitumor activity by oral administration of 20 mg/kg once daily dosing schedule for 21 days in a mouse xenograft model. The molecular docking study of 36 in the homology model of the DFG-in conformation of FLT3 resulted in a reasonable binding mode in type 1 kinases similar to the reported type 1 FLT3 inhibitors Crenolanib and Gilteritinib.
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http://dx.doi.org/10.1016/j.ejmech.2020.112205DOI Listing
June 2020

Silica dioxide nanoparticles aggravate airway inflammation in an asthmatic mouse model via NLRP3 inflammasome activation.

Regul Toxicol Pharmacol 2020 Apr 19;112:104618. Epub 2020 Feb 19.

College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju, 61186, Republic of Korea. Electronic address:

Silica dioxide nanoparticles (SiONPs) are mainly used in the rubber industry; however, they are a major air pollutant in Asia. Thus, extensive research on this issue is required. In this study, we investigated the effects of SiONPs on asthma aggravation and elucidated the underlying mechanism using ovalbumin (OVA)-induced asthmatic mice model and in NCI-H292 cells. Mice exposed to SiONPs showed markedly increased Penh values, inflammatory cell counts, and inflammatory cytokine levels compared to OVA-induced asthmatic mice. Exposure to SiONPs also induced additional airway inflammation and mucus secretion with increases in protein expression levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, and interleukin (IL)-1β compared to those in OVA-induced asthmatic mice. Treatment of SiONPs in NCI-H292 cells also significantly increased mRNA expression levels of inflammatory cytokines accompanied with elevation in the levels of TXNIP, NLRP3 inflammasome, and IL-1β proteins in a concentration-dependent manner. Taken together, exposure to SiONPs aggravated asthma development, which is closely related to inflammasome activation. Our results provide useful information about the toxicological effects of SiONPs on asthma exacerbation and suggest the need to avoid SiONP exposure especially in individuals with respiratory diseases.
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http://dx.doi.org/10.1016/j.yrtph.2020.104618DOI Listing
April 2020

Resettable skin interfaced microfluidic sweat collection devices with chemesthetic hydration feedback.

Nat Commun 2019 12 4;10(1):5513. Epub 2019 Dec 4.

Department of Materials Science and Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, 60208, USA.

Recently introduced classes of thin, soft, skin-mounted microfluidic systems offer powerful capabilities for continuous, real-time monitoring of total sweat loss, sweat rate and sweat biomarkers. Although these technologies operate without the cost, complexity, size, and weight associated with active components or power sources, rehydration events can render previous measurements irrelevant and detection of anomalous physiological events, such as high sweat loss, requires user engagement to observe colorimetric responses. Here we address these limitations through monolithic systems of pinch valves and suction pumps for purging of sweat as a reset mechanism to coincide with hydration events, microstructural optics for reversible readout of sweat loss, and effervescent pumps and chemesthetic agents for automated delivery of sensory warnings of excessive sweat loss. Human subject trials demonstrate the ability of these systems to alert users to the potential for dehydration via skin sensations initiated by sweat-triggered ejection of menthol and capsaicin.
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http://dx.doi.org/10.1038/s41467-019-13431-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892844PMC
December 2019

Soft, skin-interfaced microfluidic systems with integrated enzymatic assays for measuring the concentration of ammonia and ethanol in sweat.

Lab Chip 2020 01 28;20(1):84-92. Epub 2019 Nov 28.

Center for Bio-Integrated Electronics at the Simpson Querrey Institute for BioNanotechnology, Northwestern University, Evanston, IL 60208, USA. and Department of Materials Science and Engineering, Evanston, IL 60208, USA and Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA and Department of Chemistry, Department of Electrical Engineering and Computer Science, Department of Neurological Surgery, Simpson Querrey Institute for Nano/Biotechnology, McCormick School of Engineering and Feinberg, School of Medicine, Northwestern University, Evanston, IL 60208, USA.

Eccrine sweat is a rich and largely unexplored biofluid that contains a range of important biomarkers, from electrolytes, metabolites, micronutrients and hormones to exogenous agents, each of which can change in concentration with diet, stress level, hydration status and physiologic or metabolic state. Traditionally, clinicians and researchers have used absorbent pads and benchtop analyzers to collect and analyze the biochemical constituents of sweat in controlled, laboratory settings. Recently reported wearable microfluidic and electrochemical sensing devices represent significant advances in this context, with capabilities for rapid, in situ evaluations, in many cases with improved repeatability and accuracy. A limitation is that assays performed in these platforms offer limited control of reaction kinetics and mixing of different reagents and samples. Here, we present a multi-layered microfluidic device platform with designs that eliminate these constraints, to enable integrated enzymatic assays with demonstrations of in situ analysis of the concentrations of ammonia and ethanol in microliter volumes of sweat. Careful characterization of the reaction kinetics and their optimization using statistical techniques yield robust analysis protocols. Human subject studies with sweat initiated by warm-water bathing highlight the operational features of these systems.
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http://dx.doi.org/10.1039/c9lc01045aDOI Listing
January 2020

Soft, Skin-Interfaced Microfluidic Systems with Passive Galvanic Stopwatches for Precise Chronometric Sampling of Sweat.

Adv Mater 2019 Aug 17;31(32):e1902109. Epub 2019 Jun 17.

Department of Materials Science and Engineering, Northwestern University, Evanston, IL, 60208, USA.

Comprehensive analysis of sweat chemistry provides noninvasive health monitoring capabilities that complement established biophysical measurements such as heart rate, blood oxygenation, and body temperature. Recent developments in skin-integrated soft microfluidic systems address many challenges associated with standard technologies in sweat collection and analysis. However, recording of time-dependent variations in sweat composition requires bulky electronic systems and power sources, thereby constraining form factor, cost, and modes of use. Here, presented are unconventional design concepts, materials, and device operation principles that address this challenge. Flexible galvanic cells embedded within skin-interfaced microfluidics with passive valves serve as sweat-activated "stopwatches" that record temporal information associated with collection of discrete microliter volumes of sweat. The result allows for precise measurements of dynamic sweat composition fluctuations using in situ or ex situ analytical techniques. Integrated electronics based on near-field communication (NFC) protocols or docking stations equipped with standard electronic measurement tools provide means for extracting digital timing results from the stopwatches. Human subject studies of time-stamped sweat samples by in situ colorimetric methods and ex situ techniques based on inductively coupled plasma mass spectroscopy (ICP-MS) and chlorodimetry illustrate the ability to quantitatively capture time-dynamic sweat chemistry in scenarios compatible with field use.
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http://dx.doi.org/10.1002/adma.201902109DOI Listing
August 2019

Discovery of LDD-1075 as a potent FLT3 inhibitor.

Oncol Lett 2019 May 1;17(5):4735-4741. Epub 2019 Mar 1.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea.

Fms-like tyrosine kinase 3 (FLT3) is a valuable pharmacological target in the treatment of acute myeloid leukemia (AML). LDD-1075 and LDD-1076 are indirubin derivatives, and LDD-1075 is the ester form of LDD-1076. LDD-1076 exhibited a potent FLT3 kinase activity inhibition with an IC of 7.89 nM, whereas, LDD-1075 demonstrated a relatively weak activity against FLT3 (IC of 3.19 µM). In contrast with the results of the FLT3 kinase activity inhibition assay, the LDD-1076 did not affect the growth of the MV4-11 cell line, which harbors the constitutively activated form of the FLT3 mutation. Notably, LDD-1075 exhibited a strong cytotoxic effect against the MV4-11 cells. When LDD-1075 was incubated with the MV4-11 cell lysate, the formation of LDD-1076 was observed. Treatment with LDD-1075 inhibited the FLT3 phosphorylation along with the phosphorylation of the signal transducer and activator of transcription 5 protein, which is a downstream signal transducer of FLT3. Treatment with LDD-1075 induced apoptosis and cell cycle arrest at the G1 phase. The present study demonstrated that the LDD-1076 formed by the bioconversion of LDD-1075 is a potent FLT3 inhibitor with anti-leukemic activity.
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http://dx.doi.org/10.3892/ol.2019.10096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444428PMC
May 2019

Passive sweat collection and colorimetric analysis of biomarkers relevant to kidney disorders using a soft microfluidic system.

Lab Chip 2019 04;19(9):1545-1555

Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, MO 65211, USA.

The rich range of biomarkers in sweat and the ability to collect sweat in a non-invasive manner create interest in the use of this biofluid for assessments of health and physiological status, with potential applications that range from sports and fitness to clinical medicine. This paper introduces two important advances in recently reported classes of soft, skin-interfaced microfluidic systems for sweat capture and analysis: (1) a simple, broadly applicable means for collection of sweat that bypasses requirements for physical/mental exertion or pharmacological stimulation and (2) a set of enzymatic chemistries and colorimetric readout approaches for determining the concentrations of creatinine and urea in sweat, throughout ranges that are physiologically relevant. The results allow for routine, non-pharmacological capture of sweat for patient populations, such as infants and the elderly, that cannot be expected to sweat through exercise, and they create potential opportunities in the use of sweat for kidney disease screening/monitoring. Studies on human subjects demonstrate these essential capabilities, with quantitative comparisons to standard methods. The results expand the range of options available in microfluidic sampling and sensing of sweat for disease diagnostics and health monitoring.
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http://dx.doi.org/10.1039/c9lc00103dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830512PMC
April 2019

Battery-free, skin-interfaced microfluidic/electronic systems for simultaneous electrochemical, colorimetric, and volumetric analysis of sweat.

Sci Adv 2019 01 18;5(1):eaav3294. Epub 2019 Jan 18.

Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA.

Wearable sweat sensors rely either on electronics for electrochemical detection or on colorimetry for visual readout. Non-ideal form factors represent disadvantages of the former, while semiquantitative operation and narrow scope of measurable biomarkers characterize the latter. Here, we introduce a battery-free, wireless electronic sensing platform inspired by biofuel cells that integrates chronometric microfluidic platforms with embedded colorimetric assays. The resulting sensors combine advantages of electronic and microfluidic functionality in a platform that is significantly lighter, cheaper, and smaller than alternatives. A demonstration device simultaneously monitors sweat rate/loss, pH, lactate, glucose, and chloride. Systematic studies of the electronics, microfluidics, and integration schemes establish the key design considerations and performance attributes. Two-day human trials that compare concentrations of glucose and lactate in sweat and blood suggest a potential basis for noninvasive, semi-quantitative tracking of physiological status.
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http://dx.doi.org/10.1126/sciadv.aav3294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357758PMC
January 2019

Waterproof, electronics-enabled, epidermal microfluidic devices for sweat collection, biomarker analysis, and thermography in aquatic settings.

Sci Adv 2019 01 25;5(1):eaau6356. Epub 2019 Jan 25.

Department of Materials Science and Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA.

Noninvasive, in situ biochemical monitoring of physiological status, via the use of sweat, could enable new forms of health care diagnostics and personalized hydration strategies. Recent advances in sweat collection and sensing technologies offer powerful capabilities, but they are not effective for use in extreme situations such as aquatic or arid environments, because of unique challenges in eliminating interference/contamination from surrounding water, maintaining robust adhesion in the presence of viscous drag forces and/or vigorous motion, and preventing evaporation of collected sweat. This paper introduces materials and designs for waterproof, epidermal, microfluidic and electronic systems that adhere to the skin to enable capture, storage, and analysis of sweat, even while fully underwater. Field trials demonstrate the ability of these devices to collect quantitative in situ measurements of local sweat chloride concentration, local sweat loss (and sweat rate), and skin temperature during vigorous physical activity in controlled, indoor conditions and in open-ocean swimming.
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http://dx.doi.org/10.1126/sciadv.aau6356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357724PMC
January 2019

Soft, Skin-Integrated Multifunctional Microfluidic Systems for Accurate Colorimetric Analysis of Sweat Biomarkers and Temperature.

ACS Sens 2019 02 1;4(2):379-388. Epub 2019 Feb 1.

Department of Materials Science and Engineering , Northwestern University , Evanston , Illinois 60208 , United States.

Real-time measurements of the total loss of sweat, the rate of sweating, the temperature of sweat, and the concentrations of electrolytes and metabolites in sweat can provide important insights into human physiology. Conventional methods use manual collection processes (e.g., absorbent pads) to determine sweat loss and lab-based instrumentation to analyze its chemical composition. Although such schemes can yield accurate data, they cannot be used outside of laboratories or clinics. Recently reported wearable electrochemical devices for sweat sensing bypass these limitations, but they typically involve on-board electronics, electrodes, and/or batteries for measurement, signal processing, and wireless transmission, without direct means for measuring sweat loss or capturing and storing small volumes of sweat. Alternative approaches exploit soft, skin-integrated microfluidic systems for collection and colorimetric chemical techniques for analysis. Here, we present the most advanced platforms of this type, in which optimized chemistries, microfluidic designs, and device layouts enable accurate assessments not only of total loss of sweat and sweat rate but also of quantitatively accurate values of the pH and temperature of sweat, and of the concentrations of chloride, glucose, and lactate across physiologically relevant ranges. Color calibration markings integrated into a graphics overlayer allow precise readout by digital image analysis, applicable in various lighting conditions. Field studies conducted on healthy volunteers demonstrate the full capabilities in measuring sweat loss/rate and analyzing multiple sweat biomarkers and temperature, with performance that quantitatively matches that of conventional lab-based measurement systems.
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http://dx.doi.org/10.1021/acssensors.8b01218DOI Listing
February 2019

Bio-Integrated Wearable Systems: A Comprehensive Review.

Chem Rev 2019 04 28;119(8):5461-5533. Epub 2019 Jan 28.

Northwestern University , 2145 Sheridan Road , Evanston , Illinois 60208 , United States.

Bio-integrated wearable systems can measure a broad range of biophysical, biochemical, and environmental signals to provide critical insights into overall health status and to quantify human performance. Recent advances in material science, chemical analysis techniques, device designs, and assembly methods form the foundations for a uniquely differentiated type of wearable technology, characterized by noninvasive, intimate integration with the soft, curved, time-dynamic surfaces of the body. This review summarizes the latest advances in this emerging field of "bio-integrated" technologies in a comprehensive manner that connects fundamental developments in chemistry, material science, and engineering with sensing technologies that have the potential for widespread deployment and societal benefit in human health care. An introduction to the chemistries and materials for the active components of these systems contextualizes essential design considerations for sensors and associated platforms that appear in following sections. The subsequent content highlights the most advanced biosensors, classified according to their ability to capture biophysical, biochemical, and environmental information. Additional sections feature schemes for electrically powering these sensors and strategies for achieving fully integrated, wireless systems. The review concludes with an overview of key remaining challenges and a summary of opportunities where advances in materials chemistry will be critically important for continued progress.
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http://dx.doi.org/10.1021/acs.chemrev.8b00573DOI Listing
April 2019

Relation between blood pressure and pulse wave velocity for human arteries.

Proc Natl Acad Sci U S A 2018 10 15;115(44):11144-11149. Epub 2018 Oct 15.

Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208;

Continuous monitoring of blood pressure, an essential measure of health status, typically requires complex, costly, and invasive techniques that can expose patients to risks of complications. Continuous, cuffless, and noninvasive blood pressure monitoring methods that correlate measured pulse wave velocity (PWV) to the blood pressure via the Moens-Korteweg (MK) and Hughes Equations, offer promising alternatives. The MK Equation, however, involves two assumptions that do not hold for human arteries, and the Hughes Equation is empirical, without any theoretical basis. The results presented here establish a relation between the blood pressure and PWV that does not rely on the Hughes Equation nor on the assumptions used in the MK Equation. This relation degenerates to the MK Equation under extremely low blood pressures, and it accurately captures the results of in vitro experiments using artificial blood vessels at comparatively high pressures. For human arteries, which are well characterized by the Fung hyperelastic model, a simple formula between and PWV is established within the range of human blood pressures. This formula is validated by literature data as well as by experiments on human subjects, with applicability in the determination of blood pressure from PWV in continuous, cuffless, and noninvasive blood pressure monitoring systems.
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http://dx.doi.org/10.1073/pnas.1814392115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217416PMC
October 2018

Soft, Skin-Interfaced Microfluidic Systems with Wireless, Battery-Free Electronics for Digital, Real-Time Tracking of Sweat Loss and Electrolyte Composition.

Small 2018 11 9;14(45):e1802876. Epub 2018 Oct 9.

Center for Bio-Integrated Electronics at the Simpson, Querrey Institute for BioNanotechnology, Northwestern University, Evanston, IL, 60208, USA.

Sweat excretion is a dynamic physiological process that varies with body position, activity level, environmental factors, and health status. Conventional means for measuring the properties of sweat yield accurate results but their requirements for sampling and analytics do not allow for use in the field. Emerging wearable devices offer significant advantages over existing approaches, but each has significant drawbacks associated with bulk and weight, inability to quantify volumetric sweat rate and loss, robustness, and/or inadequate accuracy in biochemical analysis. This paper presents a thin, miniaturized, skin-interfaced microfluidic technology that includes a reusable, battery-free electronics module for measuring sweat conductivity and rate in real-time using wireless power from and data communication to electronic devices with capabilities in near field communications (NFC), including most smartphones. The platform exploits ultrathin electrodes integrated within a collection of microchannels as interfaces to circuits that leverage NFC protocols. The resulting capabilities are complementary to those of previously reported colorimetric strategies. Systematic studies of these combined microfluidic/electronic systems, accurate correlations of measurements performed with them to those of laboratory standard instrumentation, and field tests on human subjects exercising and at rest establish the key operational features and their utility in sweat analytics.
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http://dx.doi.org/10.1002/smll.201802876DOI Listing
November 2018

A fluorometric skin-interfaced microfluidic device and smartphone imaging module for in situ quantitative analysis of sweat chemistry.

Lab Chip 2018 07;18(15):2178-2186

Materials Sciences Research Center, Japan Atomic Energy Agency, Tokai, Ibaraki 319-1195, Japan.

The rich composition of solutes and metabolites in sweat and its relative ease of collection upon excretion from skin pores make this class of biofluid an attractive candidate for point of care analysis. Wearable technologies that combine electrochemical sensors with conventional or emerging semiconductor device technologies offer valuable capabilities in sweat sensing, but they are limited to assays that support amperometric, potentiometric, and colorimetric analyses. Here, we present a complementary approach that exploits fluorometric sensing modalities integrated into a soft, skin-interfaced microfluidic system which, when paired with a simple smartphone-based imaging module, allows for in situ measurement of important biomarkers in sweat. A network array of microchannels and a collection of microreservoirs pre-filled with fluorescent probes that selectively react with target analytes in sweat (e.g. probes), enable quantitative, rapid analysis. Field studies on human subjects demonstrate the ability to measure the concentrations of chloride, sodium and zinc in sweat, with accuracy that matches that of conventional laboratory techniques. The results highlight the versatility of advanced fluorescent-based imaging modalities in body-worn sweat microfluidics platforms, and they suggest some practical potential for these ideas.
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http://dx.doi.org/10.1039/c8lc00530cDOI Listing
July 2018

Mutual Destruction of Deep Lung Tumor Tissues by Nanodrug-Conjugated Stealth Mesenchymal Stem Cells.

Adv Sci (Weinh) 2018 May 26;5(5):1700860. Epub 2018 Feb 26.

Lee Gil Ya Cancer and Diabetes Institute Gachon University Incheon 21999 South Korea.

Lung cancer is a highly malignant tumor, and targeted delivery of anti-cancer drugs to deep lung tumor tissue remains a challenge in drug design. Here, it is demonstrated that bone marrow mesenchymal stem cells armed with nanodrugs are highly targeted and mutually destructive with malignant lung cancer cells and successfully eradicate lung tumors tissues. Using this approach, the current clinical dose of anti-cancer drugs for the treatment of malignant lung tumors can be decreased by more than 100-fold without triggering immunotoxicity.
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http://dx.doi.org/10.1002/advs.201700860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979625PMC
May 2018

A rapid culture system uninfluenced by an inoculum effect increases reliability and convenience for drug susceptibility testing of Mycobacterium tuberculosis.

Sci Rep 2018 06 5;8(1):8651. Epub 2018 Jun 5.

QuantaMatrix Inc., Seoul National University Hospital CMI, Jongno-gu, Seoul, 03082, Republic of Korea.

The Disc Agarose Channel (DAC) system utilizes microfluidics and imaging technologies and is fully automated and capable of tracking single cell growth to produce Mycobacterium tuberculosis (MTB) drug susceptibility testing (DST) results within 3~7 days. In particular, this system can be easily used to perform DSTs without the fastidious preparation of the inoculum of MTB cells. Inoculum effect is one of the major problems that causes DST errors. The DAC system was not influenced by the inoculum effect and produced reliable DST results. In this system, the minimum inhibitory concentration (MIC) values of the first-line drugs were consistent regardless of inoculum sizes ranging from ~10 to ~10 CFU/mL. The consistent MIC results enabled us to determine the critical concentrations for 12 anti-tuberculosis drugs. Based on the determined critical concentrations, further DSTs were performed with 254 MTB clinical isolates without measuring an inoculum size. There were high agreement rates (96.3%) between the DAC system and the absolute concentration method using Löwenstein-Jensen medium. According to these results, the DAC system is the first DST system that is not affected by the inoculum effect. It can thus increase reliability and convenience for DST of MTB. We expect that this system will be a potential substitute for conventional DST systems.
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http://dx.doi.org/10.1038/s41598-018-26419-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988837PMC
June 2018

Correction: Discovery of a FLT3 inhibitor LDD1937 as an anti-leukemic agent for acute myeloid leukemia.

Oncotarget 2018 04 13;9(28):20219. Epub 2018 Apr 13.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea.

[This corrects the article DOI: 10.18632/oncotarget.23221.].
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http://dx.doi.org/10.18632/oncotarget.25141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929457PMC
April 2018

Skin-interfaced systems for sweat collection and analytics.

Sci Adv 2018 02 16;4(2):eaar3921. Epub 2018 Feb 16.

Department of Materials Science and Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA.

Recent interdisciplinary advances in materials, mechanics, and microsystem designs for biocompatible electronics, soft microfluidics, and electrochemical biosensors establish the foundations for emerging classes of thin, skin-interfaced platforms capable of capturing, storing, and performing quantitative, spatiotemporal measurements of sweat chemistry, instantaneous local sweat rate, and total sweat loss. This review summarizes scientific and technical progress in this area and highlights the implications in real time and ambulatory modes of deployment during physical activities across a broad range of contexts in clinical health, physiology research, fitness/wellness, and athletic performance.
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http://dx.doi.org/10.1126/sciadv.aar3921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817925PMC
February 2018
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