Dr. Seung-min Park

All Publications

• Biological research and self-driving labs in deep space supported by artificial intelligence NATURE MACHINE INTELLIGENCE Sanders, L. M., Scott, R. T., Yang, J. H., Qutub, A., Garcia Martin, H., Berrios, D. C., Hastings, J. A., Rask, J., Mackintosh, G., Hoarfrost, A. L., Chalk, S., Kalantari, J., Khezeli, K., Antonsen, E. L., Babdor, J., Barker, R., Baranzini, S. E., Beheshti, A., Delgado-Aparicio, G. M., Glicksberg, B. S., Greene, C. S., Haendel, M., Hamid, A. A., Heller, P., Jamieson, D., Jarvis, K. J., Komarova, S. V., Komorowski, M., Kothiyal, P., Mahabal, A., Manor, U., Mason, C. E., Matar, M., Mias, G. I., Miller, J., Myers Jr, J. G., Nelson, C., Oribello, J., Park, S., Parsons-Wingerter, P., Prabhu, R. K., Reynolds, R. J., Saravia-Butler, A., Saria, S., Sawyer, A., Singh, N., Snyder, M., Soboczenski, F., Soman, K., Theriot, C. A., Van Valen, D., Venkateswaran, K., Warren, L., Worthey, L., Zitnik, M., Costes, S. V. 2023; 5 (3): 208-219

  View details for DOI 10.1038/s42256-023-00618-4

  View details for Web of Science ID 000974378500003

• Biomonitoring and precision health in deep space supported by artificial intelligence NATURE MACHINE INTELLIGENCE Scott, R. T., Sanders, L. M., Antonsen, E. L., Hastings, J. A., Park, S., Mackintosh, G., Reynolds, R. J., Hoarfrost, A. L., Sawyer, A., Greene, C. S., Glicksberg, B. S., Theriot, C. A., Berrios, D. C., Miller, J., Babdor, J., Barker, R., Baranzini, S. E., Beheshti, A., Chalk, S., Delgado-Aparicio, G. M., Haendel, M., Hamid, A. A., Heller, P., Jamieson, D., Jarvis, K. J., Kalantari, J., Khezeli, K., Komarova, S. V., Komorowski, M., Kothiyal, P., Mahabal, A., Manor, U., Martin, H., Mason, C. E., Matar, M., Mias, G. I., Myers Jr, J. G., Nelson, C., Oribello, J., Parsons-Wingerter, P., Prabhu, R. K., Qutub, A., Rask, J., Saravia-Butler, A., Saria, S., Singh, N., Snyder, M., Soboczenski, F., Soman, K., Van Valen, D., Venkateswaran, K., Warren, L., Worthey, L., Yang, J. H., Zitnik, M., Costes, S. V. 2023; 5 (3): 196-207

  View details for DOI 10.1038/s42256-023-00617-5

  View details for Web of Science ID 000974378500002

• Passive monitoring by smart toilets for precision health. Science translational medicine Ge, T. J., Rahimzadeh, V. N., Mintz, K., Park, W. G., Martinez-Martin, N., Liao, J. C., Park, S. M. 2023; 15 (681): eabk3489

  Abstract

  Smart toilets are a key tool for enabling precision health monitoring in the home, but such passive monitoring has ethical considerations.

  View details for DOI 10.1126/scitranslmed.abk3489

  View details for PubMedID 36724240

• Smart toilets for monitoring COVID-19 surges: passive diagnostics and public health. NPJ digital medicine Ge, T. J., Chan, C. T., Lee, B. J., Liao, J. C., Park, S. 2022; 5 (1): 39

  View details for DOI 10.1038/s41746-022-00582-0

  View details for PubMedID 35354937

• Digital biomarkers in human excreta. Nature reviews. Gastroenterology & hepatology Park, S. M., Ge, T. J., Won, D. D., Lee, J. K., Liao, J. C. 2021

  View details for DOI 10.1038/s41575-021-00462-0

  View details for PubMedID 33972768

• A mountable toilet system for personalized health monitoring via the analysis of excreta. Nature biomedical engineering Park, S. M., Won, D. D., Lee, B. J., Escobedo, D. n., Esteva, A. n., Aalipour, A. n., Ge, T. J., Kim, J. H., Suh, S. n., Choi, E. H., Lozano, A. X., Yao, C. n., Bodapati, S. n., Achterberg, F. B., Kim, J. n., Park, H. n., Choi, Y. n., Kim, W. J., Yu, J. H., Bhatt, A. M., Lee, J. K., Spitler, R. n., Wang, S. X., Gambhir, S. S. 2020

  Abstract

  Technologies for the longitudinal monitoring of a person's health are poorly integrated with clinical workflows, and have rarely produced actionable biometric data for healthcare providers. Here, we describe easily deployable hardware and software for the long-term analysis of a user's excreta through data collection and models of human health. The 'smart' toilet, which is self-contained and operates autonomously by leveraging pressure and motion sensors, analyses the user's urine using a standard-of-care colorimetric assay that traces red-green-blue values from images of urinalysis strips, calculates the flow rate and volume of urine using computer vision as a uroflowmeter, and classifies stool according to the Bristol stool form scale using deep learning, with performance that is comparable to the performance of trained medical personnel. Each user of the toilet is identified through their fingerprint and the distinctive features of their anoderm, and the data are securely stored and analysed in an encrypted cloud server. The toilet may find uses in the screening, diagnosis and longitudinal monitoring of specific patient populations.

  View details for DOI 10.1038/s41551-020-0534-9

  View details for PubMedID 32251391

• Engineered immune cells as highly sensitive cancer diagnostics NATURE BIOTECHNOLOGY Aalipour, A., Chuang, H., Murty, S., D'Souza, A. L., Park, S., Gulati, G. S., Patel, C. B., Beinat, C., Simonetta, F., Martinic, I., Gowrishankar, G., Robinson, E. R., Aalipour, E., Zhian, Z., Gambhir, S. S. 2019; 37 (5): 531-+

  View details for DOI 10.1038/s41587-019-0064-8

  View details for Web of Science ID 000469110000014

• An intravascular magnetic wire for the high-throughput retrieval of circulating tumour cells in vivo. Nature biomedical engineering Vermesh, O., Aalipour, A., Ge, T. J., Saenz, Y., Guo, Y., Alam, I. S., Park, S., Adelson, C. N., Mitsutake, Y., Vilches-Moure, J., Godoy, E., Bachmann, M., Ooi, C. C., Lyons, J. K., Mueller, K., Arami, H., Green, A., Solomon, E. I., Wang, S. X., Gambhir, S. S. 2018; 2: 696–705

  Abstract

  The detection and analysis of rare blood biomarkers is necessary for early cancer diagnosis and to facilitate the development of tailored therapies. However, current methods for the isolation of circulating tumor cells (CTCs) or nucleic acids present in a standard clinical sample of only 5-10 mL of blood provide inadequate yields for early cancer detection and comprehensive molecular profiling. We have developed a flexible magnetic wire that can retrieve rare biomarkers from the subject's blood in vivo at a much higher yield. The wire is inserted and removed through a standard intravenous catheter and captures biomarkers that have been previously labeled with injected magnetic particles. In a proof-of-concept experiment in a live porcine model, we demonstrate the in vivo labeling and single-pass capture of viable model CTCs in less than 10 seconds. The wire achieves capture efficiencies that correspond to enrichments of 10-80 times the amount of CTCs in a 5-mL blood draw, and to 500-5,000 times the enrichments achieved by the commercially available Gilupi CellCollector.

  View details for PubMedID 30524876

• Towards clinically translatable in vivo nanodiagnostics Nature Reviews Materials Park, S., Aalipour, A., Vermesh, O., Yu, J., Gambhir, S. S. 2017; 2

  View details for DOI 10.1038/natrevmats.2017.14

• Molecular profiling of single circulating tumor cells from lung cancer patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Park, S., Wong, D. J., Ooi, C. C., Kurtz, D. M., Vermesh, O., Aalipour, A., Suh, S., Pian, K. L., Chabon, J. J., Lee, S. H., Jamali, M., Say, C., Carter, J. N., Lee, L. P., Kuschner, W. G., Schwartz, E. J., Shrager, J. B., Neal, J. W., Wakelee, H. A., Diehn, M., Nair, V. S., Wang, S. X., Gambhir, S. S. 2016; 113 (52): E8379-E8386

  Abstract

  Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.

  View details for DOI 10.1073/pnas.1608461113

  View details for PubMedID 27956614

• A method for nanofluidic device prototyping using elastomeric collapse PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Park, S., Huh, Y. S., Craighead, H. G., Erickson, D. 2009; 106 (37): 15549-15554

  Abstract

  Nanofluidics represents a promising solution to problems in fields ranging from biomolecular analysis to optical property tuning. Recently a number of simple nanofluidic fabrication techniques have been introduced that exploit the deformability of elastomeric materials like polydimethylsiloxane (PDMS). These techniques are limited by the complexity of the devices that can be fabricated, which can only create straight or irregular channels normal to the direction of an applied strain. Here, we report a technique for nanofluidic fabrication based on the controlled collapse of microchannel structures. As is demonstrated, this method converts the easy to control vertical dimension of a PDMS mold to the lateral dimension of a nanochannel. We demonstrate here the creation of complex nanochannel structures as small as 60 nm and provide simple design rules for determining the conditions under which nanochannel formation will occur. The applicability of the technique to biomolecular analysis is demonstrated by showing DNA elongation in a nanochannel and a technique for optofluidic surface enhanced Raman detection of nucleic acids.

  View details for DOI 10.1073/pnas.0904004106

  View details for Web of Science ID 000269806600009

  View details for PubMedID 19717418

• Synthesis and Applications of Optical Materials. Nanomaterials (Basel, Switzerland) Park, S. M., Jun, B. H. 2023; 13 (2)

  Abstract

  As optical materials have shown outstanding physical and chemical characteristics in the bio, medical, electronics, energy and related fields of studies, the potential benefits of using these materials have been widely recognized [...].

  View details for DOI 10.3390/nano13020297

  View details for PubMedID 36678049

• Highly Bright Silica-Coated InP/ZnS Quantum Dot-Embedded Silica Nanoparticles as Biocompatible Nanoprobes. International journal of molecular sciences Ham, K., Kim, M., Bock, S., Kim, J., Kim, W., Jung, H. S., An, J., Song, H., Kim, J., Kim, H., Rho, W., Lee, S. H., Park, S., Kim, D., Jun, B. 2022; 23 (18)

  Abstract

  Quantum dots (QDs) have outstanding optical properties such as strong fluorescence, excellent photostability, broad absorption spectra, and narrow emission bands, which make them useful for bioimaging. However, cadmium (Cd)-based QDs, which have been widely studied, have potential toxicity problems. Cd-free QDs have also been studied, but their weak photoluminescence (PL) intensity makes their practical use in bioimaging challenging. In this study, Cd-free QD nanoprobes for bioimaging were fabricated by densely embedding multiple indium phosphide/zinc sulfide (InP/ZnS) QDs onto silica templates and coating them with a silica shell. The fabricated silica-coated InP/ZnS QD-embedded silica nanoparticles (SiO2@InP QDs@SiO2 NPs) exhibited hydrophilic properties because of the surface silica shell. The quantum yield (QY), maximum emission peak wavelength, and full-width half-maximum (FWHM) of the final fabricated SiO2@InP QDs@SiO2 NPs were 6.61%, 527.01 nm, and 44.62 nm, respectively. Moreover, the brightness of the particles could be easily controlled by adjusting the amount of InP/ZnS QDs in the SiO2@InP QDs@SiO2 NPs. When SiO2@InP QDs@SiO2 NPs were administered to tumor syngeneic mice, the fluorescence signal was prominently detected in the tumor because of the preferential distribution of the SiO2@InP QDs@SiO2 NPs, demonstrating their applicability in bioimaging with NPs. Thus, SiO2@InP QDs@SiO2 NPs have the potential to successfully replace Cd-based QDs as highly bright and biocompatible fluorescent nanoprobes.

  View details for DOI 10.3390/ijms231810977

  View details for PubMedID 36142888

• Lateral Flow Immunoassay with Quantum-Dot-Embedded Silica Nanoparticles for Prostate-Specific Antigen Detection. Nanomaterials (Basel, Switzerland) Bock, S., Kim, H., Kim, J., An, J., Choi, Y., Pham, X., Jo, A., Ham, K., Song, H., Kim, J., Hahm, E., Rho, W., Lee, S. H., Park, S., Lee, S., Jeong, D. H., Lee, H., Jun, B. 1800; 12 (1)

  Abstract

  Prostate cancer can be detected early by testing the presence of prostate-specific antigen (PSA) in the blood. Lateral flow immunoassay (LFIA) has been used because it is cost effective and easy to use and also has a rapid sample-to-answer process. Quantum dots (QDs) with very bright fluorescence have been previously used to improve the detection sensitivity of LFIAs. In the current study, a highly sensitive LFIA kit was devised using QD-embedded silica nanoparticles. In the present study, only a smartphone and a computer software program, ImageJ, were used, because the developed system had high sensitivity by using very bright nanoprobes. The limit of PSA detection of the developed LFIA system was 0.138 ng/mL. The area under the curve of this system was calculated as 0.852. The system did not show any false-negative result when 47 human serum samples were analyzed; it only detected PSA and did not detect alpha-fetoprotein and newborn calf serum in the samples. Additionally, fluorescence was maintained on the strip for 10 d after the test. With its high sensitivity and convenience, the devised LFIA kit can be used for the diagnosis of prostate cancer.

  View details for DOI 10.3390/nano12010033

  View details for PubMedID 35009984

• Silver-Assembled Silica Nanoparticles in Lateral Flow Immunoassay for Visual Inspection of Prostate-Specific Antigen. Sensors (Basel, Switzerland) Kim, H., Kim, J., Bock, S., An, J., Choi, Y., Pham, X., Cha, M. G., Seong, B., Kim, W., Kim, Y., Song, H., Kim, J., Park, S., Lee, S. H., Rho, W., Lee, S., Jeong, D. H., Lee, H., Jun, B. 2021; 21 (12)

  Abstract

  Prostate-specific antigen (PSA) is the best-known biomarker for early diagnosis of prostate cancer. For prostate cancer in particular, the threshold level of PSA <4.0 ng/mL in clinical samples is an important indicator. Quick and easy visual detection of the PSA level greatly helps in early detection and treatment of prostate cancer and reducing mortality. In this study, we developed optimized silica-coated silver-assembled silica nanoparticles (SiO2@Ag@SiO2 NPs) that were applied to a visual lateral flow immunoassay (LFIA) platform for PSA detection. During synthesis, the ratio of silica NPs to silver nitrate changed, and as the synthesized NPs exhibited distinct UV spectra and colors, most optimized SiO2@Ag@SiO2 NPs showed the potential for early prostate cancer diagnosis. The PSA detection limit of our LFIA platform was 1.1 ng/mL. By applying each SiO2@Ag@SiO2 NP to the visual LFIA platform, optimized SiO2@Ag@SiO2 NPs were selected in the test strip, and clinical samples from prostate cancer patients were successfully detected as the boundaries of non-specific binding were clearly seen and the level of PSA was <4 ng/mL, thus providing an avenue for quick prostate cancer diagnosis and early treatment.

  View details for DOI 10.3390/s21124099

  View details for PubMedID 34203603

• Recent Advances in Surface-Enhanced Raman Scattering Magnetic Plasmonic Particles for Bioapplications. Nanomaterials (Basel, Switzerland) Huynh, K., Hahm, E., Noh, M. S., Lee, J., Pham, X., Lee, S. H., Kim, J., Rho, W., Chang, H., Kim, D. M., Baek, A., Kim, D., Jeong, D. H., Park, S., Jun, B. 2021; 11 (5)

  Abstract

  The surface-enhanced Raman scattering (SERS) technique, that uses magnetic plasmonic particles (MPPs), is an advanced SERS detection platform owing to the synergetic effects of the particles' magnetic and plasmonic properties. As well as being an ultrasensitive and reliable SERS material, MPPs perform various functions, such as aiding in separation, drug delivery, and acting as a therapeutic material. This literature discusses the structure and multifunctionality of MPPs, which has enabled the novel application of MPPs to various biological fields.

  View details for DOI 10.3390/nano11051215

  View details for PubMedID 34064407

• Metal Nano/Microparticles for Bioapplications. International journal of molecular sciences Pham, X., Park, S., Jun, B. 2021; 22 (9)

  Abstract

  Nano/micro particles are considered to be the most valuable and important functional materials in the field of materials science and engineering [...].

  View details for DOI 10.3390/ijms22094543

  View details for PubMedID 33925269

• Overlimiting Current in Nonuniform Arrays of Microchannels: Recirculating Flow and Anticrystallization. Nano letters Lee, H., Sohn, S., Alizadeh, S., Kwon, S., Kim, T. J., Park, S., Soh, H. T., Mani, A., Kim, S. J. 2021

  Abstract

  Overlimiting current (OLC) through electrolytes interfaced with perm-selective membranes has been extensively researched for understanding fundamental nano-electrokinetics and developing efficient engineering applications. This work studies how a network of microchannels in a nonuniform array, which mimics a natural pore configuration, can contribute to OLC. Here, micro/nanofluidic devices are fabricated with arrays of parallel microchannels with nonuniform size distributions, which are faced with a perm-selective membrane. All cases maintain the same surface and bulk conduction to allow probing of the sensitivity only by the nonuniformity. Rigorous experimental and theoretical investigation demonstrates that overlimiting conductance has a maximum value depending on the nonuniformity. Furthermore, in operando visualization reveals that the nonuniform arrays induce flow loops across the microchannel network enhancing advective transport. This recirculating flow eliminates local salt accumulations so that it can effectively suppress undesirable salt crystallization. Therefore, these results can significantly advance not only the fundamental understanding of the driving mechanism of the OLC but also the design rule of electrochemical membrane applications.

  View details for DOI 10.1021/acs.nanolett.0c05049

  View details for PubMedID 33784095

• Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring. Clinical chemistry Nesvet, J. C., Antilla, K. A., Pancirer, D. S., Lozano, A. X., Preiss, J. S., Ma, W. n., Fu, A. n., Park, S. M., Gambhir, S. S., Fan, A. C., Neal, J. W., Padda, S. K., Das, M. n., Li, T. n., Wakelee, H. A., Wang, S. X. 2021

  Abstract

  Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA.We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients.The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively).The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.

  View details for DOI 10.1093/clinchem/hvaa307

  View details for PubMedID 33393992

• Noninvasive and Highly Multiplexed Five-Color Tumor Imaging of Multicore Near-Infrared Resonant Surface-Enhanced Raman Nanoparticles In Vivo. ACS nano Yu, J. H., Steinberg, I., Davis, R. M., Malkovskiy, A. V., Zlitni, A., Radzyminski, R. K., Jung, K. O., Chung, D. T., Curet, L. D., D'Souza, A. L., Chang, E., Rosenberg, J., Campbell, J., Frostig, H., Park, S. M., Pratx, G., Levin, C., Gambhir, S. S. 2021

  Abstract

  In vivo multiplexed imaging aims for noninvasive monitoring of tumors with multiple channels without excision of the tissue. While most of the preclinical imaging has provided a number of multiplexing channels up to three, Raman imaging with surface-enhanced Raman scattering (SERS) nanoparticles was suggested to offer higher multiplexing capability originating from their narrow spectral width. However, in vivo multiplexed SERS imaging is still in its infancy for multichannel visualization of tumors, which require both sufficient multiplicity and high sensitivity concurrently. Here we create multispectral palettes of gold multicore-near-infrared (NIR) resonant Raman dyes-silica shell SERS (NIR-SERRS) nanoparticle oligomers and demonstrate noninvasive and five-plex SERS imaging of the nanoparticle accumulation in tumors of living mice. We perform the five-plex ratiometric imaging of tumors by varying the administered ratio of the nanoparticles, which simulates the detection of multiple biomarkers with different expression levels in the tumor environment. Furthermore, since this method does not require the excision of tumor tissues at the imaging condition, we perform noninvasive and longitudinal imaging of the five-color nanoparticles in the tumors, which is not feasible with current ex vivo multiplexed tissue analysis platforms. Our work surpasses the multiplicity limit of previous preclinical tumor imaging methods while keeping enough sensitivity for tumor-targeted in vivo imaging and could enable the noninvasive assessment of multiple biological targets within the tumor microenvironment in living subjects.

  View details for DOI 10.1021/acsnano.1c07470

  View details for PubMedID 34797988

• Synthesis and Application of Silica-Coated Quantum Dots in Biomedicine. International journal of molecular sciences Pham, X. H., Park, S. M., Ham, K. M., Kyeong, S., Son, B. S., Kim, J., Hahm, E., Kim, Y. H., Bock, S., Kim, W., Jung, S., Oh, S., Lee, S. H., Hwang, D. W., Jun, B. H. 2021; 22 (18)

  Abstract

  Quantum dots (QDs) are semiconductor nanoparticles with outstanding optoelectronic properties. More specifically, QDs are highly bright and exhibit wide absorption spectra, narrow light bands, and excellent photovoltaic stability, which make them useful in bioscience and medicine, particularly for sensing, optical imaging, cell separation, and diagnosis. In general, QDs are stabilized using a hydrophobic ligand during synthesis, and thus their hydrophobic surfaces must undergo hydrophilic modification if the QDs are to be used in bioapplications. Silica-coating is one of the most effective methods for overcoming the disadvantages of QDs, owing to silica's physicochemical stability, nontoxicity, and excellent bioavailability. This review highlights recent progress in the design, preparation, and application of silica-coated QDs and presents an overview of the major challenges and prospects of their application.

  View details for DOI 10.3390/ijms221810116

  View details for PubMedID 34576279

• Real-time surgical margin assessment using ICG-fluorescence during laparoscopic and robot-assisted resections of colorectal liver metastases. Annals of translational medicine Achterberg, F. B., Sibinga Mulder, B. G., Meijer, R. P., Bonsing, B. A., Hartgrink, H. H., Mieog, J. S., Zlitni, A., Park, S. M., Farina Sarasqueta, A., Vahrmeijer, A. L., Swijnenburg, R. J. 2020; 8 (21): 1448

  Abstract

  Almost a third of the resections in patients with colorectal liver metastases (CRLM) undergoing curative surgery, end up being tumor-margin positive (≤1 mm margin). Near-infrared fluorescent (NIRF) imaging using the fluorescent contrast agent indocyanine green (ICG) has been studied for many different applications. When administered in a relatively low dose (10 mg) 24 hours prior to surgery, ICG accumulated in hepatocytes surrounding the CRLM. This results in the formation of a characteristic fluorescent 'rim' surrounding CRLM when located at the periphery of the liver. By resecting the metastasis with the entire surrounding fluorescent rim, in real-time guided by NIRF imaging, the surgeon can effectively acquire margin-negative (>1 mm) resections. This pilot study aims to describe the surgical technique for using near-infrared fluorescence imaging to assess tumor-margins in vivo in patients with CRLM undergoing laparoscopic or robot-assisted resections.Out of our institutional database we selected 16 CRLM based on margin-status (R0; n=8, R1; n=8), which were resected by a minimally-invasive approach using ICG-fluorescence. NIRF images acquired during surgery, from both the resection specimen and the wound bed, were analysed for fluorescent signal. We hypothesized that a protruding fluorescent rim at the parenchymal side of the resection specimen could indicate a too close proximity to the tumor and could be predictive for a tumor-positive surgical margin. NIRF images were correlated to final histopathological assessment of the resection margin.All lesions with a NIRF positive resection plane in vivo were reported as having a tumor-positive margin. Lesions that showcased no protruding rim in the wound bed in vivo were diagnosed as having a tumor-negative margin in 88% of cases. A 5-step surgical workflow is described to document the NIRF signal was used assess the resection margin in vivo for future clinical studies.The pilot study shows that image-guided surgery using real-time ICG-fluorescence has the potential to aid surgeons in achieving a tumor-negative margin in minimally invasive liver metastasectomies. The national multi-centre MIMIC-Trial will prospectively study the effect of this technique on surgical tumor-margins (Dutch Trial Register number NL7674).

  View details for DOI 10.21037/atm-20-1999

  View details for PubMedID 33313193

  View details for PubMedCentralID PMC7723628

• Publisher Correction: A mountable toilet system for personalized health monitoring via the analysis of excreta. Nature biomedical engineering Park, S. M., Won, D. D., Lee, B. J., Escobedo, D. n., Esteva, A. n., Aalipour, A. n., Ge, T. J., Kim, J. H., Suh, S. n., Choi, E. H., Lozano, A. X., Yao, C. n., Bodapati, S. n., Achterberg, F. B., Kim, J. n., Park, H. n., Choi, Y. n., Kim, W. J., Yu, J. H., Bhatt, A. M., Lee, J. K., Spitler, R. n., Wang, S. X., Gambhir, S. S. 2020

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41551-020-0562-5

  View details for PubMedID 32382068

• Emerging ultrafast nucleic acid amplification technologies for next-generation molecular diagnostics. Biosensors & bioelectronics Lee, S. H., Park, S. M., Kim, B. N., Kwon, O. S., Rho, W. Y., Jun, B. H. 2019; 141: 111448

  Abstract

  Over the last decade, nucleic acid amplification tests (NAATs) including polymerase chain reaction (PCR) were an indispensable methodology for diagnosing cancers, viral and bacterial infections owing to their high sensitivity and specificity. Because the NAATs can recognize and discriminate even a few copies of nucleic acid (NA) and species-specific NA sequences, NAATs have become the gold standard in a wide range of applications. However, limitations of NAAT approaches have recently become more apparent by reason of their lengthy run time, large reaction volume, and complex protocol. To meet the current demands of clinicians and biomedical researchers, new NAATs have developed to achieve ultrafast sample-to-answer protocols for the point-of-care testing (POCT). In this review, ultrafast NA-POCT platforms are discussed, outlining their NA amplification principles as well as delineating recent advances in ultrafast NAAT applications. The main focus is to provide an overview of NA-POCT platforms in regard to sample preparation of NA, NA amplification, NA detection process, interpretation of the analysis, and evaluation of the platform design. Increasing importance will be given to innovative, ultrafast amplification methods and tools which incorporate artificial intelligence (AI)-associated data analysis processes and mobile-healthcare networks. The future prospects of NA POCT platforms are promising as they allow absolute quantitation of NA in individuals which is essential to precision medicine.

  View details for DOI 10.1016/j.bios.2019.111448

  View details for PubMedID 31252258

• An intravascular magnetic wire for the high-throughput retrieval of circulating tumour cells in vivo. Nature biomedical engineering Vermesh, O., Aalipour, A., Ge, T. J., Saenz, Y., Guo, Y., Alam, I. S., Park, S. M., Adelson, C. N., Mitsutake, Y., Vilches-Moure, J., Godoy, E., Bachmann, M. H., Ooi, C. C., Lyons, J. K., Mueller, K., Arami, H., Green, A., Solomon, E. I., Wang, S. X., Gambhir, S. S. 2018; 2 (9): 696-705

  Abstract

  The detection and analysis of rare blood biomarkers is necessary for early diagnosis of cancer and to facilitate the development of tailored therapies. However, current methods for the isolation of circulating tumour cells (CTCs) or nucleic acids present in a standard clinical sample of only 5-10 ml of blood provide inadequate yields for early cancer detection and comprehensive molecular profiling. Here, we report the development of a flexible magnetic wire that can retrieve rare biomarkers from the subject's blood in vivo at a much higher yield. The wire is inserted and removed through a standard intravenous catheter and captures biomarkers that have been previously labelled with injected magnetic particles. In a proof-of-concept experiment in a live porcine model, we demonstrate the in vivo labelling and single-pass capture of viable model CTCs in less than 10 s. The wire achieves capture efficiencies that correspond to enrichments of 10-80 times the amount of CTCs in a 5-ml blood draw, and 500-5,000 times the enrichments achieved using the commercially available Gilupi CellCollector.

  View details for DOI 10.1038/s41551-018-0257-3

  View details for PubMedID 30505627

  View details for PubMedCentralID PMC6261517

• High-Density Lipoprotein Nanoparticle Imaging in Atherosclerotic Vascular Disease. JACC. Basic to translational science Leeper, N. J., Park, S. M., Smith, B. R. 2017; 2 (1): 98-100

  Abstract

  Nanoparticles promise to advance the field of cardiovascular theranostics. However, their sustained and targeted delivery remains an important obstacle. The body synthesizes some "natural" nanoparticles, including high-density lipoprotein (HDL), which may home to the atherosclerotic plaque and promote cholesterol efflux. In a recent article published in JACC: Cardiovascular Imaging, investigators generated modified, radiolabeled HDL nanoparticles and confirmed they accumulated in atherosclerotic lesions from several different species. These approaches hold promise for the noninvasive diagnosis of vulnerable plaque and in the stratification of patients in whom HDL-mimetic therapy may have a clinical benefit.

  View details for DOI 10.1016/j.jacbts.2017.01.005

  View details for PubMedID 30167557

  View details for PubMedCentralID PMC6113536

• Multigene Profiling of Single Circulating Tumor Cells Molecular & Cellular Oncology Park, S., Wong, D., Ooi, C., Nesvet, J., Nair, V. S., Wang, S. X., Gambhir, S. S. 2017; 4 (2): e1289295

  Abstract

  Numerous techniques for isolating circulating tumor cells (CTCs) have been developed. Concurrently, single-cell techniques that can reveal molecular components of CTCs have become widely available. We discuss how the combination of isolation and multigene profiling of single CTCs in our platform can facilitate eventual translation to the clinic.

  View details for DOI 10.1080/23723556.2017.1289295

  View details for PubMedCentralID PMC5383366

• High-throughput full-length single-cell mRNA-seq of rare cells. PloS one Ooi, C. C., Mantalas, G. L., Koh, W. n., Neff, N. F., Fuchigami, T. n., Wong, D. J., Wilson, R. J., Park, S. M., Gambhir, S. S., Quake, S. R., Wang, S. X. 2017; 12 (11): e0188510

  Abstract

  Single-cell characterization techniques, such as mRNA-seq, have been applied to a diverse range of applications in cancer biology, yielding great insight into mechanisms leading to therapy resistance and tumor clonality. While single-cell techniques can yield a wealth of information, a common bottleneck is the lack of throughput, with many current processing methods being limited to the analysis of small volumes of single cell suspensions with cell densities on the order of 107 per mL. In this work, we present a high-throughput full-length mRNA-seq protocol incorporating a magnetic sifter and magnetic nanoparticle-antibody conjugates for rare cell enrichment, and Smart-seq2 chemistry for sequencing. We evaluate the efficiency and quality of this protocol with a simulated circulating tumor cell system, whereby non-small-cell lung cancer cell lines (NCI-H1650 and NCI-H1975) are spiked into whole blood, before being enriched for single-cell mRNA-seq by EpCAM-functionalized magnetic nanoparticles and the magnetic sifter. We obtain high efficiency (> 90%) capture and release of these simulated rare cells via the magnetic sifter, with reproducible transcriptome data. In addition, while mRNA-seq data is typically only used for gene expression analysis of transcriptomic data, we demonstrate the use of full-length mRNA-seq chemistries like Smart-seq2 to facilitate variant analysis of expressed genes. This enables the use of mRNA-seq data for differentiating cells in a heterogeneous population by both their phenotypic and variant profile. In a simulated heterogeneous mixture of circulating tumor cells in whole blood, we utilize this high-throughput protocol to differentiate these heterogeneous cells by both their phenotype (lung cancer versus white blood cells), and mutational profile (H1650 versus H1975 cells), in a single sequencing run. This high-throughput method can help facilitate single-cell analysis of rare cell populations, such as circulating tumor or endothelial cells, with demonstrably high-quality transcriptomic data.

  View details for PubMedID 29186152

  View details for PubMedCentralID PMC5706670

• Deactivated CRISPR Associated Protein 9 for Minor-Allele Enrichment in Cell-Free DNA. Clinical chemistry Aalipour, A. n., Dudley, J. C., Park, S. M., Murty, S. n., Chabon, J. J., Boyle, E. A., Diehn, M. n., Gambhir, S. S. 2017

  Abstract

  Cell-free DNA (cfDNA) diagnostics are emerging as a new paradigm of disease monitoring and therapy management. The clinical utility of these diagnostics is relatively limited by a low signal-to-noise ratio, such as with low allele frequency (AF) mutations in cancer. While enriching for rare alleles to increase their AF before sample analysis is one strategy that can greatly improve detection capability, current methods are limited in their generalizability, ease of use, and applicability to point mutations.Leveraging the robust single-base-pair specificity and generalizability of the CRISPR associated protein 9 (Cas9) system, we developed a deactivated Cas9 (dCas9)-based method of minor-allele enrichment capable of efficient single-target and multiplexed enrichment. The dCas9 protein was complexed with single guide RNAs targeted to mutations of interest and incubated with cfDNA samples containing mutant strands at low abundance. Mutation-bound dCas9 complexes were isolated, dissociated, and the captured DNA purified for downstream use.Targeting the 3 most common epidermal growth factor receptor mutations (exon 19 deletion, T790M, L858R) found in nonsmall-cell lung cancer (NSCLC), we achieved >20-fold increases in AF and detected mutations by use of qPCR at an AF of 0.1%. In a cohort of 18 NSCLC patient-derived cfDNA samples, our method enabled detection of 8 out of 13 mutations that were otherwise undetected by qPCR.The dCas9 method provides important application of the CRISPR/Cas9 system outside the realm of genome editing and can provide a step forward for the detection capability of cfDNA diagnostics.

  View details for PubMedID 29038154

• Capture and Genetic Analysis of Circulating Tumor Cells Using a Magnetic Separation Device (Magnetic Sifter). Methods in molecular biology (Clifton, N.J.) Ooi, C. C., Park, S. M., Wong, D. J., Gambhir, S. S., Wang, S. X. 2017; 1634: 153–62

  Abstract

  Circulating tumor cells (CTCs) are currently widely studied for their potential application as part of a liquid biopsy. These cells are shed from the primary tumor into the circulation, and are postulated to provide insight into the molecular makeup of the actual tumor in a minimally invasive manner. However, they are extremely rare in blood, with typical concentrations of 1-100 in a milliliter of blood; hence, a need exists for a rapid and high-purity method for isolating CTCs from whole blood. Here, we describe the application of a microfabricated magnetic sifter toward isolation of CTCs from whole blood at volumetric flow rates of 10 mL/h, along with the use of a PDMS-based nanowell system for single-cell gene expression profiling. This method allows rapid isolation of CTCs and subsequent integration with downstream genetic profiling methods for clinical applications such as targeted therapy, therapy monitoring, or further biological studies.

  View details for PubMedID 28819848

• Dual transcript and protein quantification in a massive single cell array. Lab on a chip Park, S., Lee, J. Y., Hong, S., Lee, S. H., Dimov, I. K., Lee, H., Suh, S., Pan, Q., Li, K., Wu, A. M., Mumenthaler, S. M., Mallick, P., Lee, L. P. 2016; 16 (19): 3682-3688

  Abstract

  Recently, single-cell molecular analysis has been leveraged to achieve unprecedented levels of biological investigation. However, a lack of simple, high-throughput single-cell methods has hindered in-depth population-wide studies with single-cell resolution. We report a microwell-based cytometric method for simultaneous measurements of gene and protein expression dynamics in thousands of single cells. We quantified the regulatory effects of transcriptional and translational inhibitors on cMET mRNA and cMET protein in cell populations. We studied the dynamic responses of individual cells to drug treatments, by measuring cMET overexpression levels in individual non-small cell lung cancer (NSCLC) cells with induced drug resistance. Across NSCLC cell lines with a given protein expression, distinct patterns of transcript-protein correlation emerged. We believe this platform is applicable for interrogating the dynamics of gene expression, protein expression, and translational kinetics at the single-cell level - a paradigm shift in life science and medicine toward discovering vital cell regulatory mechanisms.

  View details for DOI 10.1039/c6lc00762g

  View details for PubMedID 27546183

  View details for PubMedCentralID PMC5221609

• Pref-1 Marks Very Early Mesenchymal Precursors Required for Adipose Tissue Development and Expansion CELL REPORTS Hudak, C. S., Gulyaeva, O., Wang, Y., Park, S., Lee, L., Kang, C., Sul, H. S. 2014; 8 (3): 678-687

  Abstract

  Pref-1 is an EGF-repeat-containing protein that inhibits adipocyte differentiation. To better understand the origin and development of white adipose tissue (WAT), we generated transgenic mouse models for transient or permanent fluorescent labeling of cells using the Pref-1 promoter, facilitating inducible ablation. We show that Pref-1-marked cells retain proliferative capacity and are very early adipose precursors, prior to expression of Zfp423 or PPARγ. In addition, the Pref-1-marked cells establish that adipose precursors are mesenchymal, but not endothelial or pericytal, in origin. During embryogenesis, Pref-1-marked cells first appear in the dorsal mesenteric region as early as embryonic day 10.5 (E10.5). These cells become lipid-laden adipocytes at E17.5 in the subcutaneous region, whereas visceral WAT develops after birth. Finally, ablation of Pref-1-marked cells prevents not only embryonic WAT development but also later adult adipose expansion upon high-fat feeding, demonstrating the requirement of Pref-1 cells for adipogenesis.

  View details for DOI 10.1016/j.celrep.2014.06.060

  View details for Web of Science ID 000341572200005

  View details for PubMedID 25088414

  View details for PubMedCentralID PMC4138044

• Toward Integrated Molecular Diagnostic System (iMDx): Principles and Applications IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Park, S., Sabour, A. F., Son, J. H., Lee, S. H., Lee, L. P. 2014; 61 (5): 1506-1521

  Abstract

  Integrated molecular diagnostic systems ( iMDx), which are automated, sensitive, specific, user-friendly, robust, rapid, easy-to-use, and portable, can revolutionize future medicine. This review will first focus on the components of sample extraction, preservation, and filtration necessary for all point-of-care devices to include for practical use. Subsequently, we will look for low-powered and precise methods for both sample amplification and signal transduction, going in-depth to the details behind their principles. The final field of total device integration and its application to the clinical field will also be addressed to discuss the practicality for future patient care. We envision that microfluidic systems hold the potential to breakthrough the number of problems brought into the field of medical diagnosis today.

  View details for DOI 10.1109/TBME.2014.2309119

  View details for Web of Science ID 000335150300015

  View details for PubMedID 24759281

  View details for PubMedCentralID PMC4141683

• Hemolysis-free blood plasma separation LAB ON A CHIP Son, J. H., Lee, S. H., Hong, S., Park, S., Lee, J., Dickey, A. M., Lee, L. P. 2014; 14 (13): 2287-2292

  Abstract

  Hemolysis, involving the rupture of red blood cells (RBCs) and release of their contents into blood plasma, is a major issue of concern in clinical fields. Hemolysis in vitro can occur as a result of errors in clinical trials; in vivo, hemolysis can be caused by a variety of medical conditions. Blood plasma separation is often the first step in blood-based clinical diagnostic procedures. However, inhibitors released from RBCs due to hemolysis during plasma separation can lead to problems in diagnostic tests such as low sensitivity, selectivity and inaccurate results. In particular, a general lack of simple and reliable blood plasma separation methods has been a major obstacle for microfluidic-based point-of-care (POC) diagnostic devices. Here we present a hemolysis-free microfluidic blood plasma separation platform. A membrane filter was positioned on top of a vertical up-flow channel (filter-in-top configuration) to reduce clogging of RBCs by gravity-assisted cells sedimentation. With this device, separated plasma volume was increased approximately 4-fold (2.4 μL plasma after 20 min with 38% hematocrit human whole blood), and hemoglobin concentration in separated plasma was decreased approximately 90% due to the prevention of RBCs hemolysis, when compared to conventional filter-in-bottom configuration blood plasma separation platforms. On-chip plasma contained ~90% of protein and ~100% of nucleic acids found in off-chip centrifuged plasma, confirming comparable target molecule recovery efficiency. This simple and robust on-chip blood plasma separation device integrates with downstream detection modules to ultimately create sample-to-answer microfluidic POC diagnostics devices.

  View details for DOI 10.1039/c4lc00149d

  View details for Web of Science ID 000337096800017

  View details for PubMedID 24825250

• Discriminating cellular heterogeneity using microwell-based RNA cytometry. Nature communications Dimov, I. K., Lu, R., Lee, E. P., Seita, J., Sahoo, D., Park, S., Weissman, I. L., Lee, L. P. 2014; 5: 3451-?

  View details for DOI 10.1038/ncomms4451

  View details for PubMedID 24667995

• Optical Methods in Studies of Olfactory System Bioelectronic Nose Lee, S., Park, S., Lee, L. P. Springer. 2014: 191–220

  View details for DOI 10.1007/978-94-017-8613-3_11

• Rapid Prototyping of Nanofluidic Systems Using Size-Reduced Electrospun Nanofibers for Biomolecular Analysis SMALL Park, S., Huh, Y. S., Szeto, K., Joe, D. J., Kameoka, J., Coates, G. W., Edel, J. B., Erickson, D., Craighead, H. G. 2010; 6 (21): 2420-2426

  Abstract

  Biomolecular transport in nanofluidic confinement offers various means to investigate the behavior of biomolecules in their native aqueous environments, and to develop tools for diverse single-molecule manipulations. Recently, a number of simple nanofluidic fabrication techniques has been demonstrated that utilize electrospun nanofibers as a backbone structure. These techniques are limited by the arbitrary dimension of the resulting nanochannels due to the random nature of electrospinning. Here, a new method for fabricating nanofluidic systems from size-reduced electrospun nanofibers is reported and demonstrated. As it is demonstrated, this method uses the scanned electrospinning technique for generation of oriented sacrificial nanofibers and exposes these nanofibers to harsh, but isotropic etching/heating environments to reduce their cross-sectional dimension. The creation of various nanofluidic systems as small as 20 nm is demonstrated, and practical examples of single biomolecular handling, such as DNA elongation in nanochannels and fluorescence correlation spectroscopic analysis of biomolecules passing through nanochannels, are provided.

  View details for DOI 10.1002/smll.201000884

  View details for Web of Science ID 000284016700012

  View details for PubMedID 20878634

• Selection and elution of aptamers using nanoporous sol-gel arrays with integrated microheaters LAB ON A CHIP Park, S., Ahn, J., Jo, M., Lee, D., Lis, J. T., Craighead, H. G., Kim, S. 2009; 9 (9): 1206-1212

  Abstract

  RNA and DNA aptamers that bind to target molecules with high specificity and affinity have been a focus of diagnostics and therapeutic research. These aptamers are obtained by SELEX (Systematic Evolution of Ligands by EXponential enrichment) often requiring more than 10 successive cycles of selection and amplification, where each cycle normally takes 2 days per cycle of SELEX. Here, we have demonstrated the use of sol-gel arrays of proteins in a microfluidic system for efficient selection of RNA aptamers against multiple target molecules. The microfluidic chip incorporates five sol-gel binding droplets, within which specific target proteins are imbedded. The droplets are patterned on top of individually addressable electrical microheaters used for selective elution of aptamers bound to target proteins in the sol-gel droplets. We demonstrate that specific aptamers bind their respective protein targets and can be selectively eluted by micro-heating. Finally, our microfluidic SELEX system greatly improved selection efficiency, reducing the number of selection cycles needed to produce high affinity aptamers. The process is readily scalable to larger arrays of sol-gel-embedded proteins. To our knowledge, this is the first demonstration of a chip-based selection of aptamers using microfluidics, thereby allowing development of a high throughput and efficient SELEX procedures.

  View details for DOI 10.1039/b814993c

  View details for Web of Science ID 000265223200008

  View details for PubMedID 19370238

• On-chip coupling of electrochemical pumps and an SU-8 tip for electrospray ionization mass spectrometry BIOMEDICAL MICRODEVICES Park, S., Lee, K. H., Craighead, H. G. 2008; 10 (6): 891-897

  Abstract

  We present the integration of a cyclo olefin copolymer microfluidic chip with electrochemical pumps and an SU-8 tip for electrospray ionization mass spectrometry. The electrochemical pump, using electrolysis as an internal pressure source, was fabricated directly on the surface of the polymer chip. The triangular SU-8 emitter tip was fabricated on a glass wafer using standard photolithography. After release from the glass wafer, this tip was aligned to the microchannel and bonded between two polymer plates. The electrochemical pump and the electrospray tip were tested with electrospray ionization mass spectrometry. Mass spectrometry confirmed the stability of the electrochemical pump and the electrospray tip.

  View details for DOI 10.1007/s10544-008-9203-6

  View details for Web of Science ID 000259246400013

  View details for PubMedID 18563570

• Microfluidic encapsulated nanoelectromechanical resonators JOURNAL OF VACUUM SCIENCE & TECHNOLOGY B Aubin, K. L., Huang, J., Park, S., Yang, Y., Kondratovich, M., Craighead, H. G., Ilic, B. R. 2007; 25 (4): 1171-1174

  View details for DOI 10.1116/1.2746333

  View details for Web of Science ID 000249170100013