Publications by authors named "Ishan Barman"

91 Publications

Vibrational spectroscopy for decoding cancer microbiota interactions: Current evidence and future perspective.

Semin Cancer Biol 2021 Jul 14. Epub 2021 Jul 14.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. Electronic address:

The role of human microbiota in cancer initiation and progression is recognized in recent years. In order to investigate the interactions between cancer cells and microbes, a systematic analysis using various emerging techniques is required. Owing to the label-free, non-invasive and molecular fingerprinting characteristics, vibrational spectroscopy is uniquely suited to decode and understand the relationship and interactions between cancer and the microbiota at the molecular level. In this review, we first provide a quick overview of the fundamentals of vibrational spectroscopic techniques, namely Raman and infrared spectroscopy. Next, we discuss the emerging evidence underscoring utilities of these spectroscopic techniques to study cancer or microbes separately, and share our perspective on how vibrational spectroscopy can be employed at the intersection of the two fields. Finally, we envision the potential opportunities in exploiting vibrational spectroscopy not only in basic cancer-microbiome research but also in its clinical translation, and discuss the challenges in the bench to bedside translation.
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http://dx.doi.org/10.1016/j.semcancer.2021.07.004DOI Listing
July 2021

Role of Aqueous-Phase Calcination in Synthesis of Ultra-Stable Dye-Embedded Fluorescent Nanoparticles for Cellular Probing.

Appl Spectrosc 2021 Aug 12;75(8):1012-1021. Epub 2021 Jul 12.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA.

Fluorescence imaging is a major driver of discovery in biology, and an invaluable asset in clinical diagnostics. To overcome quenching limitations of conventional fluorescent dyes and further improve intensity, nanoparticle-based constructs have been the subject of intense investigation, and within this realm, dye-doped silica-coated nanoparticles have garnered significant attention. Despite their growing popularity in research, fluorescent silica nanoparticles suffer from a significant flaw. The degradation of these nanoparticles in biological media by hydrolytic dissolution is underreported, leading to serious misinterpretations, and limiting their applicability for live cell and in vivo imaging. Here, the development of an ultra-stable, dye-embedded, silica-coated metal nanoparticle is reported, and its superior performance in long-term live cell imaging is demonstrated. While conventional dye-doped silica nanoparticles begin to degrade within an hour in aqueous media, by leveraging a modified liquid calcination process, this new construct is shown to be stable for at least 24 h. The stability of this metal-enhanced fluorescent probe in biologically relevant temperatures and media, and its demonstrated utility for cell imaging, paves the way for its future adoption in biomedical research.
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http://dx.doi.org/10.1177/00037028211027597DOI Listing
August 2021

Raman and quantitative phase imaging allow morpho-molecular recognition of malignancy and stages of B-cell acute lymphoblastic leukemia.

Biosens Bioelectron 2021 Oct 12;190:113403. Epub 2021 Jun 12.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD, 21287, USA. Electronic address:

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies that account for nearly one-third of all pediatric cancers. The current diagnostic assays are time-consuming, labor-intensive, and require expensive reagents. Here, we report a label-free approach featuring diffraction phase imaging and Raman microscopy that can retrieve both morphological and molecular attributes for label-free optical phenotyping of individual B cells. By investigating leukemia cell lines of early and late stages along with the healthy B cells, we show that phase images can capture subtle morphological differences among the healthy, early, and late stages of leukemic cells. By exploiting its biomolecular specificity, we demonstrate that Raman microscopy is capable of accurately identifying not only different stages of leukemia cells but also individual cell lines at each stage. Overall, our study provides a rationale for employing this hybrid modality to screen leukemia cells using the widefield QPI and using Raman microscopy for accurate differentiation of early and late-stage phenotypes. This contrast-free and rapid diagnostic tool exhibits great promise for clinical diagnosis and staging of leukemia in the near future.
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http://dx.doi.org/10.1016/j.bios.2021.113403DOI Listing
October 2021

Advancing Raman spectroscopy from research to clinic: Translational potential and challenges.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Nov 13;260:119957. Epub 2021 May 13.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, United States; The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States; Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, United States. Electronic address:

Raman spectroscopy has emerged as a non-invasive and versatile diagnostic technique due to its ability to provide molecule-specific information with ultrahigh sensitivity at near-physiological conditions. Despite exhibiting substantial potential, its translation from optical bench to clinical settings has been impacted by associated limitations. This perspective discusses recent clinical and biomedical applications of Raman spectroscopy and technological advancements that provide valuable insights and encouragement for resolving some of the most challenging hurdles.
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http://dx.doi.org/10.1016/j.saa.2021.119957DOI Listing
November 2021

Spectroscopy-Assisted Label-free Molecular Analysis of Live Cell Surface with Vertically Aligned Plasmonic Nanopillars.

Small 2021 05 4;17(21):e2100161. Epub 2021 May 4.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

A generalized label-free platform for surface-selective molecular sensing in living cells can transform the ability to examine complex events in the cell membrane. While vertically aligned semiconductor and metal-semiconductor hybrid nanopillars have rapidly surfaced for stimulating and probing the intracellular environment, the potential of such constructs for selectively interrogating the cell membrane is surprisingly underappreciated. In this work, a new platform, entitled nano-PROD (nano-pillar based Raman optical detection), enables molecular recording by probing fundamental vibrational modes of membrane constituents of cells adherent on a large-area silver-coated silicon nanopillar substrate fabricated using a precursor solution-based nanomanufacturing process. It is shown that the nano-PROD platform sustains live cells in near-physiological conditions, which can be directly profiled using surface-enhanced Raman spectroscopy due to the confined electromagnetic field enhancement. The experimental results highlight the utility of the platform in probing specific cell surface markers for accurately recognizing the phenotypically identical prostate cancer cells, differing only in prostate-specific membrane antigen expression. Due to its tunability, nano-PROD has the promise to be readily extendable to other applications that can leverage its unique combination of nanoscale topographic features and molecular sensing capabilities, from stain-free cytopathology inspection to understanding spatio-mechanical regulation in membrane receptor function.
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http://dx.doi.org/10.1002/smll.202100161DOI Listing
May 2021

Utilizing pulse dynamics for non-invasive Raman spectroscopy of blood analytes.

Biosens Bioelectron 2021 May 26;180:113115. Epub 2021 Feb 26.

Department of Metrology and Optoelectronics, Faculty of Electronics, Telecommunications, and Informatics, Gdańsk University of Technology, G. Narutowicza 11/12, 80-233, Gdańsk, Poland.

Non-invasive measurement methods offer great benefits in the field of medical diagnostics with molecular-specific techniques such as Raman spectroscopy which is increasingly being used for quantitative measurements of tissue biochemistry in vivo. However, some important challenges still remain for label-free optical spectroscopy to be incorporated into the clinical laboratory for routine testing. In particular, non-analyte-specific variations in tissue properties introduce significant variability of the spectra, thereby preventing reliable calibration. For measurements of blood analytes such as glucose, we propose to decrease the interference from individual tissue characteristics by exploiting the known dynamics of the blood-tissue matrix. We reason that by leveraging the natural blood pulse rhythm, the signals from the blood analytes can be enhanced while those from the static components can be effectively suppressed. Here, time-resolved measurements with subsequent pulse frequency estimation and phase-sensitive detection are proposed to recover the Raman spectra correlated with the dynamic changes at blood-pulse frequency. Pilot in vivo study results are presented to establish the benefits as well as outline the challenges of the proposed method in terms of instrumentation and signal processing.
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http://dx.doi.org/10.1016/j.bios.2021.113115DOI Listing
May 2021

Silver-coated silicon nanowire platform discriminates genomic DNA from normal and malignant human epithelial cells using label-free Raman spectroscopy.

Mater Sci Eng C Mater Biol Appl 2021 Mar 6;122:111951. Epub 2021 Feb 6.

Institute for Microelectronics and Microsystems, CNR, 00133 Rome, Italy. Electronic address:

Genomic deoxyribonucleic acid (DNA) stores and carries the information required to maintain and replicate cellular life. While much efforts have been devoted in decoding the sequence of DNA basis to detect the genetic mutations related to cancer disease, it is becoming clear that physical properties, like structural conformation, stiffness and shape, can play an important role to recognize DNA modifications. Here, silver-coated silicon nanowires (Ag/SiNWs) are exploited as Raman spectroscopic platform to easily discriminate healthy and cancer genomic DNA, extracted from human normal skin and malignant melanoma cells, respectively. In particular, aqueous DNA droplets are directly deposited onto a forest of Ag/SiNWs and Raman maps are acquired after sample dehydration. By applying principal component analysis (PCA) to the Raman spectra collected within the droplets, healthy and cancer cell DNA can be distinguished without false negative identifications and with few false positive results (< 2%). The discrimination occurs regardless the analysis of specific DNA sequencing, but through Raman bands strictly related to the interfacing of the DNA and the NWs. The observed phenomenon can be ascribed to conformational differences and/or diverse charge properties between healthy and cancer cell DNA determining a different arrangement of the molecules adsorbed onto the NWs upon water evaporation. The unique interaction with DNA and facile fabrication technology make Ag/SiNWs an effective platform for a robust, rapid and label-free cancer diagnosis, as well as a potential tool to investigate physical properties of DNA.
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http://dx.doi.org/10.1016/j.msec.2021.111951DOI Listing
March 2021

Lithium from breast-milk inhibits thyroid iodine uptake and hormone production, which are remedied by maternal iodine supplementation.

Bipolar Disord 2021 Jan 28. Epub 2021 Jan 28.

Department of Physics, City University of Hong Kong, Hong Kong SAR, China.

Background: Lithium is especially taken as a maintenance medication for Bipolar Disorder. In women with bipolar disorder, lithium is often effective during postpartum period, but breast-feeding for medicated mothers is controversial because of harmful effects for her child. At present, the biological mechanisms of lithium are not well-understood, affecting its usage and overall health implications.

Procedure: We developed a rat lithium and breast-feeding model at human therapeutic levels to study the effects of lithium exposure through breast-milk on pups' thyroid function. Novel laser analytical spectroscopy, along with traditional blood and immunohistochemical tests, were applied to further investigate the mechanisms behind the thyroid dysfunction. Maternal iodine supplementation was evaluated as a therapeutic method to address the pups' thyroid dysfunction.

Results: Pups exposed to lithium via breastmilk, even with the dam on a sub-therapeutic level, experienced weight gain, reduced blood thyroxine (T ), and elevated blood urea nitrogen, indicating effects on thyroid and kidney function. We show that lithium inhibited iodine uptake by thyroid follicles, initiating a mechanism that reduced iodination of tyrosine, thyroglobulin cleavage, and thyroid hormone production. Importantly, infant thyroid function can be significantly improved by administering supplementary iodine to the medicated dam's diet during breast-feeding.

Conclusion: These results elucidate the mechanisms of lithium in thyroid function, provide valuable information on use postpartum, and suggest a clinically applicable remedy to side-effects. The results are particularly important for patients (and their infants) who respond well to lithium and need, or choose, to breast-feed.
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http://dx.doi.org/10.1111/bdi.13047DOI Listing
January 2021

A Programmable DNA-Silicification-Based Nanocavity for Single-Molecule Plasmonic Sensing.

Adv Mater 2021 Feb 18;33(7):e2005133. Epub 2021 Jan 18.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

Plasmonic nanocavities are highly desirable for optical sensing because of their singular ability to confine light into deep subwavelength volumes. Yet, it remains profoundly challenging to fabricate structurally resilient nanocavities with high fidelity, and to obtain direct, noninvasive visualization of the plasmonic hotspots within such constructs. Herein, highly precise and robust nanocavities, entitled DNA-silicified template for Raman optical beacon (DNA-STROBE), are engineered by using silicified DNA scaffolds for spatial organization of discrete plasmonic nanoparticles. In addition to substantially enhancing structural stability and chemical inertness, DNA silicification significantly improves nanogap control, resulting simultaneously in large and controlled local electromagnetic field enhancement. The ultrasmall mode volume of the DNA-STROBE constructs promotes single-molecule occupancy enabling surface-enhanced Raman spectroscopy (SERS) observations of single-molecule activity even at elevated background concentration, significantly relaxing the restrictive pico- to nanomolar molecular concentration condition typically required for such investigations. Additionally, leveraging super-resolution SERS measurements allows noninvasive and diffraction-unlimited spatial profiling of otherwise unresolvable plasmonic hotspots. The highly programmable and reproducible nature of the DNA-STROBE, coupled with its quantitative label-free molecular readouts, provides a versatile platform with applications across the spectrum of nanophotonics and biomedical sciences.
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http://dx.doi.org/10.1002/adma.202005133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275373PMC
February 2021

Molecular Radiative Energy Shifts under Strong Oscillating Fields.

Small 2021 01 23;17(3):e2007244. Epub 2020 Dec 23.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

Coherent manipulation of light-matter interactions is pivotal to the advancement of nanophotonics. Conventionally, the non-resonant optical Stark effect is harnessed for band engineering by intense laser pumping. However, this method is hindered by the transient Stark shifts and the high-energy laser pumping which, by itself, is precluded as a nanoscale optical source due to light diffraction. As an analog of photons in a laser, surface plasmons are uniquely positioned to coherently interact with matter through near-field coupling, thereby, providing a potential source of electric fields. Herein, the first demonstration of plasmonic Stark effect is reported and attributed to a newly uncovered energy-bending mechanism. As a complementary approach to the optical Stark effect, it is envisioned that the plasmonic Stark effect will advance fundamental understanding of coherent light-matter interactions and will also provide new opportunities for advanced optoelectronic tools, such as ultrafast all-optical switches and biological nanoprobes at lower light power levels.
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http://dx.doi.org/10.1002/smll.202007244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099018PMC
January 2021

Laser induced breakdown spectroscopy with machine learning reveals lithium-induced electrolyte imbalance in the kidneys.

J Pharm Biomed Anal 2021 Feb 5;194:113805. Epub 2020 Dec 5.

Department of Physics, City University of Hong Kong, Hong Kong SAR, China. Electronic address:

Lithium is a major psychiatric medication, especially as long-term maintenance medication for Bipolar Disorder. Despite its effectiveness, lithium has side-effects, such as on renal function. In this study, lithium was administered to adult rats. This animal model of renal function was validated by measuring blood lithium, urea nitrogen (BUN), and thyroxine (T) using inductively-coupled plasma mass spectrometry and enzyme-linked immunosorbent assay. The kidneys were analyzed by laser induced breakdown spectroscopy (LIBS) with 1064 nm ablation and 300-900 nm detection. Principal components analysis (PCA), radial visualization, and random forest classification were performed on the LIBS spectra for multi-element prediction and classification. Lithium at 0.34 mmol/L was detected in the blood of lithium treated subjects only. BUN was increased (6.6 vs. 5.3 mmol/L) and T decreased (58.12 vs. 51.4 mmol/L) in the blood of lithium subjects compared with controls, indicating renal abnormalities. LIBS detected lithium at 2.3 mmol/kg in the kidneys of lithium subjects only. Calcium was also observed to be reduced in lithium subjects, compared with controls. Subsequent PCA observed a change in the balance of sodium and potassium in the kidneys. These are key electrolytes in the body. Importantly, partial least squares regression showed that standard clinical measurements, such as the blood tests, can be used to predict kidney electrolyte measurements, which typically cannot be performed in humans. Overall, lithium accumulates in the kidneys and adversely affects renal function. The effects are likely related to electrolyte imbalance. LIBS with machine learning analysis has potential to improve clinical management of renal side-effects in patients on lithium medication.
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http://dx.doi.org/10.1016/j.jpba.2020.113805DOI Listing
February 2021

Furin-Mediated Self-Assembly of Olsalazine Nanoparticles for Targeted Raman Imaging of Tumors.

Angew Chem Int Ed Engl 2021 02 26;60(8):3923-3927. Epub 2021 Jan 26.

The Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Olsalazine (Olsa) is a broad-spectrum anti-cancer agent acting as a DNA-methylation inhibitor. When conjugated to 2-cyano-6-aminobenzothiazole and a peptide substrate specific for the tumor-overexpressed enzyme furin, it can self-assemble into nanoparticles that can be detected by chemical-exchange saturation-transfer magnetic-resonance imaging (CEST MRI). We report here that these nano-assemblies can also be detected with high specificity in furin-overexpressing tumor cells by Raman spectroscopy with a distinct scattering signature and demonstrate the utility of this sensing mechanism in vitro and in vivo. Our findings suggest that Raman spectroscopy could be used for high-resolution image-guided surgery to precisely delineate tumor margins during and after resection in real-time as well as to determine microscopic tumor invasion and multifocal locoregional tumor spread, which are currently impossible to visualize with available imaging technologies, including CEST MRI.
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http://dx.doi.org/10.1002/anie.202014839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902394PMC
February 2021

Coarse Raman and optical diffraction tomographic imaging enable label-free phenotyping of isogenic breast cancer cells of varying metastatic potential.

Biosens Bioelectron 2021 Mar 27;175:112863. Epub 2020 Nov 27.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD, 21287, USA. Electronic address:

Identification of the metastatic potential represents one of the most important tasks for molecular imaging of cancer. While molecular imaging of metastases has witnessed substantial progress as an area of clinical inquiry, determining precisely what differentiates the metastatic phenotype has proven to be more elusive. In this study, we utilize both the morphological and molecular information provided by 3D optical diffraction tomography and Raman spectroscopy, respectively, to propose a label-free route for optical phenotyping of cancer cells at single-cell resolution. By using an isogenic panel of cell lines derived from MDA-MB-231 breast cancer cells that vary in their metastatic potential, we show that 3D refractive index tomograms can capture subtle morphological differences among the parental, circulating tumor cells, and lung metastatic cells. By leveraging its molecular specificity, we demonstrate that coarse Raman microscopy is capable of rapidly mapping a sufficient number of cells for training a random forest classifier that can accurately predict the metastatic potential of cells at a single-cell level. We also perform multivariate curve resolution alternating least squares decomposition of the spectral dataset to demarcate spectra from cytoplasm and nucleus, and test the feasibility of identifying metastatic phenotypes using the spectra only from the cytoplasmic and nuclear regions. Overall, our study provides a rationale for employing coarse Raman mapping to substantially reduce measurement time thereby enabling the acquisition of reasonably large training datasets that hold the key for label-free single-cell analysis and, consequently, for differentiation of indolent from aggressive phenotypes.
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http://dx.doi.org/10.1016/j.bios.2020.112863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847362PMC
March 2021

Silver-Coated Disordered Silicon Nanowires Provide Highly Sensitive Label-Free Glycated Albumin Detection through Molecular Trapping and Plasmonic Hotspot Formation.

Adv Healthc Mater 2021 02 25;10(3):e2001110. Epub 2020 Nov 25.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

Glycated albumin (GA) is rapidly emerging as a robust biomarker for screening and monitoring of diabetes. To facilitate its rapid, point-of-care measurements, a label-free surface-enhanced Raman spectroscopy (SERS) sensing platform is reported that leverages the specificity of molecular vibrations and signal amplification on silver-coated silicon nanowires (Ag/SiNWs) for highly sensitive and reproducible quantification of GA. The simulations and experimental measurements demonstrate that the disordered orientation of the nanowires coupled with the wicking of the analyte molecules during the process of solvent evaporation facilitates molecular trapping at the generated plasmonic hotspots. Highly sensitive detection of glycated albumin is shown with the ability to visually detect spectral features at as low as 500 × 10 m, significantly below the physiological range of GA in body fluids. Combined with chemometric regression models, the spectral data recorded on the Ag/SiNWs also allow accurate prediction of glycated concentration in mixtures of glycated and non-glycated albumin in proportions that reflect those in the bloodstream.
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http://dx.doi.org/10.1002/adhm.202001110DOI Listing
February 2021

Identification and Staging of B-Cell Acute Lymphoblastic Leukemia Using Quantitative Phase Imaging and Machine Learning.

ACS Sens 2020 10 14;5(10):3281-3289. Epub 2020 Oct 14.

Connecticut Children's Innovation Center, University of Connecticut School of Medicine, Farmington, Connecticut 06032, United States.

Identification and classification of leukemia cells in a rapid and label-free fashion is clinically challenging and thus presents a prime arena for implementing new diagnostic tools. Quantitative phase imaging, which maps optical path length delays introduced by the specimen, has been demonstrated to discern cellular phenotypes based on differential morphological attributes. Rapid acquisition capability and the availability of label-free images with high information content have enabled researchers to use machine learning (ML) to reveal latent features. We developed a set of ML classifiers, including convolutional neural networks, to discern healthy B cells from lymphoblasts and classify stages of B cell acute lymphoblastic leukemia. Here, we show that the average dry mass and volume of normal B cells are lower than those of cancerous cells and that these morphologic parameters increase further alongside disease progression. We find that the relaxed training requirements of a ML approach are conducive to the classification of cell type, with minimal space, training time, and memory requirements. Our findings pave the way for a larger study on clinical samples of acute lymphoblastic leukemia, with the overarching goal of its broader use in hematopathology, where the prospect of objective diagnoses with minimal sample preparation remains highly desirable.
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http://dx.doi.org/10.1021/acssensors.0c01811DOI Listing
October 2020

Cancer cells display increased migration and deformability in pace with metastatic progression.

FASEB J 2020 07 28;34(7):9307-9315. Epub 2020 May 28.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA.

In this study, we explored the relation between metastatic states vs the capacity of confined migration, amoeboid transition, and cellular stiffness. We compared across an isogenic panel of human breast cancer cells derived from MDA-MB-231 cells. It was observed that cells after lung metastasis have the fastest migration and lowest stiffness, with a significantly higher capacity to transition into an amoeboid mode. Our findings illustrate that metastasis is a selective process favoring motile and softer cells. Moreover, the observation that circulating tumor cells resemble the parental cell line, but not lung-metastatic cells, suggests that cells with higher deformability and motility are likely selected during extravasation and colonization.
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http://dx.doi.org/10.1096/fj.202000101RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547847PMC
July 2020

A Fluorescence and Surface-Enhanced Raman Spectroscopic Dual-Modal Aptasensor for Sensitive Detection of Cyanotoxins.

ACS Sens 2020 05 29;5(5):1419-1426. Epub 2020 Apr 29.

Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, United States.

The ability to detect trace analytes without necessitating solid surface attachment or complicated processing steps would facilitate the translation of sensors for monitoring environmental toxins in the field. To address a critical unmet need in fresh water ecology, we have developed a dual-modal aptamer-based biosensor (aptasensor), featuring fluorescence and surface-enhanced Raman spectroscopy (SERS), for sensitive and selective detection of hepatotoxin microcystin-LR (MC-LR). The rational sensor design is based on the high affinity of the cyanine (Cy3) dye-modified complementary DNA (Cy3-cDNA) strand toward the plasmonic gold nanostars (GNSs) in comparison to the Cy3-cDNA/aptamer duplex. The preferential binding of MC-LR toward the MC-LR-specific aptamer triggers the dissociation of Cy3-cDNA/aptamer duplexes, which switches the Cy3's fluorescence "off" and SERS "on" due to the proximity of Cy3 dye to the GNS surface. Both fluorescence and SERS intensities are observed to vary linearly with the MC-LR concentration over the range of investigation. We have achieved high sensitivity and excellent specificity with the aptasensor toward MC-LR, which can be attributed to the fluorescence quenching effect, significant SERS enhancement by the GNSs, and the high affinity of the aptamer toward the MC-LR analytes. We further demonstrate the applicability of the present aptasensor for detection of MC-LR in a diverse set of real water samples with high accuracy and excellent reproducibility. With further refinement, we believe that the aptamer-driven complementary assembly of the SERS and fluorescence sensing constructs can be applied for rapid, multiplexed, and robust measurements of environmental toxins in the field.
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http://dx.doi.org/10.1021/acssensors.0c00307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560972PMC
May 2020

Single red blood cell analysis reveals elevated hemoglobin in poikilocytes.

J Biomed Opt 2020 01;25(1):1-13

City Univ. of Hong Kong, China.

Abnormally shaped red blood cells (RBCs), called poikilocytes, can cause anemia. At present, the biochemical abnormalities in poikilocytes are not well understood. Normal RBCs and poikilocytes were analyzed using whole-blood and single-cell methods. Poikilocytes were induced in rat blood by intragastrically administering titanium dioxide (TiO) nanoparticles. Complete blood count and inductively coupled plasma mass spectrometry analyses were performed on whole-blood to measure average RBC morphology, blood hemoglobin (HGB), iron content, and other blood parameters. Follow-up confocal Raman spectroscopy was performed on single RBCs to analyze cell-type-specific HGB content. Two types of poikilocytes, acanthocytes and echinocytes, were observed in TiO blood samples, along with normal RBCs. Acanthocytes (diameter 7.7  ±  0.5  μm) and echinocytes (7.6  ±  0.6  μm) were microscopically larger (  <  0.05) than normal RBCs (6.6  ±  0.4  μm) found in control blood samples (no TiO administration). Similarly, mean corpuscular volume was higher (  <  0.05) in TiO whole-blood (70.70  ±  1.97  fl) than in control whole-blood (67.42  ±  2.03  fl). Poikilocytes also had higher HGB content. Mean corpuscular hemoglobin was higher (  <  0.05) in TiO whole-blood (21.84  ±  0.75  pg) than in control whole-blood (20.8  ±  0.32  pg). Iron content was higher (  <  0.001) in TiO whole-blood (697.0  ±  24.5  mg  /  l) than in control whole-blood (503.4  ±  38.5  mg  /  l), which supports elevated HGB as iron is found in HGB. HGB-associated Raman bands at 1637, 1585, and 1372  cm had higher (  <  0.001) amplitudes in acanthocytes and echinocytes than in RBCs from control blood and normal RBCs from TiO blood. Further, the 1585-cm band had a lower (  <  0.05) amplitude in normal RBCs from TiO versus control RBCs. This represents biochemical abnormalities in normal appearing RBCs. Overall, poikilocytes, especially acanthocytes, have elevated HGB.
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http://dx.doi.org/10.1117/1.JBO.25.1.015004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976897PMC
January 2020

Rapid, Label-free Optical Spectroscopy Platform for Diagnosis of Heparin-Induced Thrombocytopenia.

Angew Chem Int Ed Engl 2020 04 19;59(15):5972-5978. Epub 2020 Feb 19.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

The use of surface-enhanced Raman spectroscopy (SERS) to determine spectral markers for the diagnosis of heparin-induced thrombocytopenia (HIT), a difficult-to-diagnose immune-related complication that often leads to limb ischemia and thromboembolism, is proposed. The ability to produce distinct molecular signatures without the addition of labels enables unbiased inquiry and makes SERS an attractive complementary diagnostic tool. A capillary-tube-derived SERS platform offers ultrasensitive, label-free measurement as well as efficient handling of blood serum samples. This shows excellent reproducibility, long-term stability and provides an alternative diagnostic rubric for the determination of HIT by leveraging machine-learning-based classification of the spectroscopic data. We envision that a portable Raman instrument could be combined with the capillary-tube-based SERS analytical tool for diagnosis of HIT in the clinical laboratory, without perturbing the existing diagnostic workflow.
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http://dx.doi.org/10.1002/anie.201913970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547846PMC
April 2020

Optical properties of symmetry-breaking tetrahedral nanoparticles.

Nanoscale 2020 Jan;12(2):832-842

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.

Spectrally rich but geometrically simple plasmonic metallic nanoparticles are highly favored in nanophotonics. However, they remain elusive owing to the symmetry-induced mode degeneracy and interband transition-induced plasmonic damping. Hence, most nanoparticles exhibit a single major extinction peak originating from the lowest-order dipole resonance. In this study, we uncover that even a simple tetrahedral nanoparticle supports rich spectral features due to symmetry breaking. This discovery runs counter to the reported gold tetrahedral nanoparticles, where only a single extinction peak was observed. We find that, in the case of a tetrahedral nanoparticle, the plasmonic quadrupole vertex mode becomes a bright mode and hybridizes with the dipole vertex mode, which splits the extinction peak and contributes to spectral diversity and tunability. The peak splitting is also found to be sensitively dependent on the roundness of vertices and edges. Furthermore, the tetrahedral depolarization factors are determined using the previously generalized absorption coefficient. We envision that this work will not only help fill the gap in understanding the optical properties enriched by symmetry breaking but also guide the superior probe design by combining spectral tunability with geometric simplicity of the nanoparticle.
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http://dx.doi.org/10.1039/c9nr08515gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560971PMC
January 2020

Towards rational design and optimization of near-field enhancement and spectral tunability of hybrid core-shell plasmonic nanoprobes.

Sci Rep 2019 11 5;9(1):16071. Epub 2019 Nov 5.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA.

In biology, sensing is a major driver of discovery. A principal challenge is to create a palette of probes that offer near single-molecule sensitivity and simultaneously enable multiplexed sensing and imaging in the "tissue-transparent" near-infrared region. Surface-enhanced Raman scattering and metal-enhanced fluorescence have shown substantial promise in addressing this need. Here, we theorize a rational design and optimization strategy to generate nanostructured probes that combine distinct plasmonic materials sandwiching a dielectric layer in a multilayer core shell configuration. The lower energy resonance peak in this multi-resonant construct is found to be highly tunable from visible to the near-IR region. Such a configuration also allows substantially higher near-field enhancement, compared to a classical core-shell nanoparticle that possesses a single metallic shell, by exploiting the differential coupling between the two core-shell interfaces. Combining such structures in a dimer configuration, which remains largely unexplored at this time, offers significant opportunities not only for near-field enhancement but also for multiplexed sensing via the (otherwise unavailable) higher order resonance modes. Together, these theoretical calculations open the door for employing such hybrid multi-layered structures, which combine facile spectral tunability with ultrahigh sensitivity, for biomolecular sensing.
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http://dx.doi.org/10.1038/s41598-019-52418-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831636PMC
November 2019

Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy.

Nat Mater 2019 12 21;18(12):1376-1383. Epub 2019 Oct 21.

The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Among the strategies used for enhancement of tumour retention of imaging agents or anticancer drugs is the rational design of probes that undergo a tumour-specific enzymatic reaction preventing them from being pumped out of the cell. Here, the anticancer agent olsalazine (Olsa) was conjugated to the cell-penetrating peptide RVRR. Taking advantage of a biologically compatible condensation reaction, single Olsa-RVRR molecules were self-assembled into large intracellular nanoparticles by the tumour-associated enzyme furin. Both Olsa-RVRR and Olsa nanoparticles were readily detected with chemical exchange saturation transfer magnetic resonance imaging by virtue of exchangeable Olsa hydroxyl protons. In vivo studies using HCT116 and LoVo murine xenografts showed that the OlsaCEST signal and anti-tumour therapeutic effect were 6.5- and 5.2-fold increased, respectively, compared to Olsa without RVRR, with an excellent 'theranostic correlation' (R = 0.97) between the imaging signal and therapeutic response (normalized tumour size). This furin-targeted, magnetic resonance imaging-detectable platform has potential for imaging tumour aggressiveness, drug accumulation and therapeutic response.
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http://dx.doi.org/10.1038/s41563-019-0503-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872935PMC
December 2019

Rapid, quantitative determination of aggregation and particle formation for antibody drug conjugate therapeutics with label-free Raman spectroscopy.

Anal Chim Acta 2019 Nov 10;1081:138-145. Epub 2019 Jul 10.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Lot release and stability testing of biologics are essential parts of the quality control strategy for ensuring therapeutic material dosed to patients is safe and efficacious, and consistent with previous clinical and toxicological experience. Characterization of protein aggregation is of particular significance, as aggregates may lose the intrinsic pharmaceutical properties as well as engage with the immune system instigating undesirable downstream immunogenicity. While important, real-time identification and quantification of subvisible particles in the monoclonal antibody (mAb) drug products remains inaccessible with existing techniques due to limitations in measurement time, sensitivity or experimental conditions. Here, owing to its exquisite molecular specificity, non-perturbative nature and lack of sample preparation requirements, we propose label-free Raman spectroscopy in conjunction with multivariate analysis as a solution to this unmet need. By leveraging subtle, but consistent, differences in vibrational modes of the biologics, we have developed a support vector machine-based regression model that provides fast, accurate prediction for a wide range of protein aggregations. Moreover, in blinded experiments, the model shows the ability to precisely differentiate between aggregation levels in mAb like product samples pre- and post-isothermal incubation, where an increase in aggregate levels was experimentally determined. In addition to offering fresh insights into mAb like product-specific aggregation mechanisms that can improve engineering of new protein therapeutics, our results highlight the potential of Raman spectroscopy as an in-line analytical tool for monitoring protein particle formation.
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http://dx.doi.org/10.1016/j.aca.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750807PMC
November 2019

Decoding Live Cell Interactions with Multi-Nanoparticle Systems: Differential Implications for Uptake, Trafficking, and Gene Regulation.

ACS Appl Mater Interfaces 2019 Sep 4;11(37):33659-33666. Epub 2019 Sep 4.

Department of Mechanical Engineering , Johns Hopkins University , Baltimore , Maryland 21218 , United States.

Surface modification with oligonucleotides renders gold nanoparticles to endocytose through very different pathways as compared to unmodified ones. Such oligonucleotide-modified gold nanoparticles (OGNs) have been exploited as effective nanocarriers for gene regulation therapies. Notably, in an effort to reduce overall dosage and provide safer transition to the clinic, cooperative systems composed of two or more discrete nanomaterials have been recently proposed as an alternative to intrinsically multifunctional nanoparticles. Yet, our understanding of such systems designed to synergistically cooperate in their diagnostic or therapeutic functions remains acutely limited. Specifically, cellular interactions and uptake of OGNs are poorly understood when the cell simultaneously interacts with other types of nanoparticles. Here, we investigated the impact of simultaneous uptake of similar-sized iron oxide nanoparticles (IOPs) on the endocytosis and gene regulation function of OGNs, whose analogues have been proposed for sensitization, targeting, and treatment of tumors. We discovered that both the OGN uptake amount and, remarkably, the gene regulation function remained stable when exposed to a very wide range of extracellular concentrations of IOPs. Additionally, the co-localization analysis showed that a proportion of OGNs was co-localized with IOPs inside cells, which hints at the presence of similar trafficking pathways for OGNs and IOPs following endocytosis. Taken together, our observations indicate that while the OGN endocytosis is highly independent of the IOP endocytosis, it shares transport pathways inside cells-but does so without affecting the gene regulation behavior. These results provide key insights into concomitant interactions of cells with diverse nanoparticles and offer a basis for the future design and optimization of cooperative nanomaterials for diverse theranostic applications.
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http://dx.doi.org/10.1021/acsami.9b11315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776239PMC
September 2019

Composite-Scattering Plasmonic Nanoprobes for Label-Free, Quantitative Biomolecular Sensing.

Small 2019 09 8;15(38):e1901165. Epub 2019 Aug 8.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

Biosensing based on localized surface plasmon resonance (LSPR) relies on concentrating light to a nanometeric spot and leads to a highly enhanced electromagnetic field near the metal nanostructure. Here, a design of plasmonic nanostructures based on rationally structured metal-dielectric combinations is presented, called composite scattering probes (CSPs), to generate an integrated multimodal biosensing platform featuring LSPR and surface-enhanced Raman spectroscopy (SERS). Specifically, CSP configurations are proposed, which have several prominent resonance peaks enabling higher tunability and sensitivity for self-referenced multiplexed analyte sensing. Using electron-beam evaporation and thermal dewetting, large-area, uniform, and tunable CSPs are fabricated, which are suitable for label-free LSPR and SERS measurements. The CSP prototypes are used to demonstrate refractive index sensing and molecular analysis using albumin as a model analyte. By using partial least squares on recorded absorption profiles, differentiation of subtle changes in refractive index (as low as 0.001) in the CSP milieu is demonstrated. Additionally, CSPs facilitate complementary untargeted plasmon-enhanced Raman measurements from the sample's compositional contributors. With further refinement, it is envisioned that the method may lead to a sensitive, versatile, and tunable platform for quantitative concentration determination and molecular fingerprinting, particularly where limited a priori information of the sample is available.
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http://dx.doi.org/10.1002/smll.201901165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759334PMC
September 2019

Shedding Light on the Trehalose-Enabled Mucopermeation of Nanoparticles with Label-Free Raman Spectroscopy.

Small 2019 08 3;15(33):e1901679. Epub 2019 Jul 3.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

Nanoparticle-based drug delivery systems have attracted significant interest owing to their promise as tunable platforms that offer improved intracellular release of cargo therapeutics. However, significant challenges remain in maintaining the physiological stability of the mucosal matrix due to the nanoparticle-induced reduction in the matrix diffusivity and promotion of mucin aggregation. Such aggregation also adversely impacts the permeability of the nanoparticles, and thus, diminishes the efficacy of nanoparticle-based formulations. Here, an entirely complementary approach is proposed to the existing nanoparticle functionalization methods to address these challenges by using trehalose, a naturally occurring disaccharide that offers exceptional protein stabilization. Plasmon-enhanced Raman spectroscopy and far-red fluorescence emission of the plasmonic silver nanoparticulate clusters are harnessed to create a unique dual-functional, aggregating, and imaging agent that obviates the need of an additional reporter to investigate mucus-nanoparticle interactions. These spectroscopy-based density mapping tools uncover the mechanism of mucus-nanoparticle interactions and establish the protective role of trehalose microenvironment in minimizing the nanoparticle aggregation. Thus, in contrast to the prevailing belief, these results demonstrate that nonfunctionalized nanoparticles may rapidly penetrate through mucus barriers, and by leveraging the bioprotectant attributes of trehalose, an in vivo milieu for efficient mucosal drug delivery can be generated.
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http://dx.doi.org/10.1002/smll.201901679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697627PMC
August 2019

Ultrasensitive Detection of Hepatotoxic Microcystin Production from Cyanobacteria Using Surface-Enhanced Raman Scattering Immunosensor.

ACS Sens 2019 05 23;4(5):1203-1210. Epub 2019 Apr 23.

School of Materials Science and Engineering, State Key Laboratory for Power Metallurgy , Central South University , Changsha , Hunan 410083 , China.

Microcystin-LR (MC-LR) is considered the most common hazardous toxin produced during harmful algal blooms. In addition to potential risk of long-term exposure to low concentrations in drinking water, acute toxicity due to MC-LR resulting from algal blooms could result in fatalities in rare cases. Although several methods are currently available to detect MC-LR, development of a low-cost, ultrasensitive measurement method would help limit exposure by enabling early detection and continuous monitoring of MC-LR. Here, we develop a surface-enhanced Raman scattering (SERS) spectroscopic immunosensor for detection and quantification of the hepatotoxic MC-LR toxin in aquatic settings with excellent robustness, selectivity, and sensitivity. We demonstrate that the developed SERS sensor can reach a limit of detection (0.014 μg/L) at least 1 order of magnitude lower and display a linear dynamic detection range (0.01 μg/L to 100 μg/L) 2 orders of magnitude wider in comparison to the commercial enzyme-linked immunosorbent assay test. The superior analytical performance of this SERS immunosensor enables monitoring of the dynamic production of MC-LR from a Microcystis aeruginosa culture. We believe that the present method could serve as a useful tool for detection of hepatotoxic microcystin toxins in various aquatic settings such as drinking water, lakes, and reservoirs. Further development of this technique could result in single-cell microcystin resolution or real-time monitoring to mitigate the associated toxicity and economic loss.
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http://dx.doi.org/10.1021/acssensors.8b01453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776237PMC
May 2019

Label-Free Raman Spectroscopy Reveals Signatures of Radiation Resistance in the Tumor Microenvironment.

Cancer Res 2019 04 28;79(8):2054-2064. Epub 2019 Feb 28.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland.

Delay in the assessment of tumor response to radiotherapy continues to pose a major challenge to quality of life for patients with nonresponsive tumors. Here, we exploited label-free Raman spectroscopic mapping to elucidate radiation-induced biomolecular changes in tumors and uncovered latent microenvironmental differences between treatment-resistant and -sensitive tumors. We used isogenic radiation-resistant and -sensitive A549 human lung cancer cells and human head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-47 and UM-SCC-22B, respectively) to grow tumor xenografts in athymic nude mice and demonstrated the molecular specificity and quantitative nature of Raman spectroscopic tissue assessments. Raman spectra obtained from untreated and treated tumors were subjected to chemometric analysis using multivariate curve resolution-alternating least squares (MCR-ALS) and support vector machine (SVM) to quantify biomolecular differences in the tumor microenvironment. The Raman measurements revealed significant and reliable differences in lipid and collagen content postradiation in the tumor microenvironment, with consistently greater changes observed in the radiation-sensitive tumors. In addition to accurately evaluating tumor response to therapy, the combination of Raman spectral markers potentially offers a route to predicting response in untreated tumors prior to commencing treatment. Combined with its noninvasive nature, our findings provide a rationale for studies using Raman spectroscopy, with the ultimate goal of clinical translation for patient stratification and guiding adaptation of radiotherapy during the course of treatment. SIGNIFICANCE: These findings highlight the sensitivity of label-free Raman spectroscopy to changes induced by radiotherapy and indicate the potential to predict radiation resistance prior to commencing therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467810PMC
April 2019

Reagent-Free and Rapid Assessment of T Cell Activation State Using Diffraction Phase Microscopy and Deep Learning.

Anal Chem 2019 03 22;91(5):3405-3411. Epub 2019 Feb 22.

Connecticut Children's Innovation Center , University of Connecticut School of Medicine , Farmington , Connecticut 06032 , United States.

CD8 T cells constitute an essential compartment of the adaptive immune system. During immune responses, naı̈ve T cells become functional, as they are primed with their cognate determinants by the antigen presenting cells. Current methods of identifying activated CD8 T cells are laborious, time-consuming and expensive due to the extensive list of required reagents. Here, we demonstrate an optical imaging approach featuring quantitative phase imaging to distinguish activated CD8 T cells from naı̈ve CD8 T cells in a rapid and reagent-free manner. We measured the dry mass of live cells and employed transport-based morphometry to better understand their differential morphological attributes. Our results reveal that, upon activation, the dry cell mass of T cells increases significantly in comparison to that of unstimulated cells. By employing deep learning formalism, we are able to accurately predict the population ratios of unknown mixed population based on the acquired quantitative phase images. We envision that, with further refinement, this label-free method of T cell phenotyping will lead to a rapid and cost-effective platform for assaying T cell responses to candidate antigens in the near future.
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http://dx.doi.org/10.1021/acs.analchem.8b04895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423970PMC
March 2019

Self-Folding Hybrid Graphene Skin for 3D Biosensing.

Nano Lett 2019 03 19;19(3):1409-1417. Epub 2018 Nov 19.

Department of Materials Science and Engineering , Johns Hopkins University , Baltimore , Maryland 21218 , United States.

Biological samples such as cells have complex three-dimensional (3D) spatio-molecular profiles and often feature soft and irregular surfaces. Conventional biosensors are based largely on 2D and rigid substrates, which have limited contact area with the entirety of the surface of biological samples making it challenging to obtain 3D spatially resolved spectroscopic information, especially in a label-free manner. Here, we report an ultrathin, flexible skinlike biosensing platform that is capable of conformally wrapping a soft or irregularly shaped 3D biological sample such as a cancer cell or a pollen grain, and therefore enables 3D label-free spatially resolved molecular spectroscopy via surface-enhanced Raman spectroscopy (SERS). Our platform features an ultrathin thermally responsive poly( N-isopropylacrylamide)-graphene-nanoparticle hybrid skin that can be triggered to self-fold and wrap around 3D micro-objects in a conformal manner due to its superior flexibility. We highlight the utility of this 3D biosensing platform by spatially mapping the 3D molecular signatures of a variety of microparticles including silica microspheres, spiky pollen grains, and human breast cancer cells.
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http://dx.doi.org/10.1021/acs.nanolett.8b03461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432654PMC
March 2019
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