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Geomagnetism, similar to other areas of geophysics, is an observation-based science. Data agreement between comparative geomagnetic vector observations is one of the most important evaluation criteria for high-quality geomagnetic data. The main influencing factors affecting the agreement between comparative observational data are the attitude angle, scale factor, long-term time drift, and temperature. In this paper, we propose a method based on a genetic algorithm and linear regression to correct for these effects and use the distribution pattern of points in Bland–Altman plots with a 95% confidence interval length to qualitatively and quantitatively evaluate the agreement between the comparative observational data. In Bland–Altman plots with better agreement, that is, with the corrected data, more than 95% of the points are distributed within the 95% confidence interval and there is no obvious pattern in the distribution of the points. Meanwhile, the length of 95% confidence interval decreased significantly after the correction. The method presented here has positive effects on the vector instrumentation detection and would enhance the robustness of geomagnetic observatory by bringing the data quality of the backup variometer data in line with the primary variometer. Graphical Abstract

Cell-free DNA has been widely used in non-invasive prenatal diagnostics (NIPD) nowadays. Compared to these incomplete and multi-source DNA fragments, fetal nucleated red blood cells (fNRBCs), once as an aided biomarker to monitor potential fetal pathological conditions, have re-attracted research interest in NIPD because of their definite fetal source and the total genetic information contained in the nuclei. Isolating these fetal cells from maternal peripheral blood and subsequent cell-based bio-analysis make maximal genetic diagnosis possible, while causing minimal harm to the fetus or its mother. In this paper, an affinity microchip is reported which uses hydroxyapatite/chitosan nanoparticles as well as immuno-agent anti-CD147 to effectively isolate fNRBCs from maternal peripheral blood, and on-chip biomedical analysis was demonstrated as a proof of concept for NIPD based on fNRBCs. Tens of fNRBCs can be isolated from 1 mL of peripheral blood (almost 25 mL-1 in average) from normal pregnant women (from the 10th to 30th gestational week). The diagnostic application of fNRBCs for fetal chromosome disorders (Trisomy 13 and 21) was also demonstrated. Our method offers effective isolation and accurate analysis of fNRBCs to implement comprehensive NIPD and to enhance insights into fetal cell development.

Detection of detached fetal nucleated red blood cells (fNRBCs) in the maternal peripheral blood may serve as a prospective testing method competing with the cell-free DNA, in non-invasive prenatal testing (NIPT). Methods: Herein, we introduce a facile and effective lab-on-a-chip method of fNRBCs detection using a capture-releasing material that is composed of biotin-doped polypyrrole nanoparticles. To enhance local topographic interactions between the nano-components and fNRBC, a specific antibody, CD147, coated on the nanostructured substrate led to the isolation of fNRBCs from maternal peripheral blood. Subsequently, an electrical system was employed to release the captured cells using 0.8 V for 15 s. The diagnostic application of fNRBCs for fetal chromosomal disorders (Trisomy 13/21/18/X syndrome, microdeletion syndrome) was demonstrated. Results: Cells captured by nanostructured microchips were identified as fNRBCs. Twelve cases of chromosomal aneuploidies and one case of 18q21 microdeletion syndrome were diagnosed using the fNRBCs released from the microchips. Conclusion: Our method offers effective and accurate analysis of fNRBCs for comprehensive NIPT to monitor fetal cell development.

Background: Circulating tumor cells (CTCs) are a burgeoning topic in cancer biomarker discovery research with minimal invasive blood draws. CTCs can be used as potential biomarkers for disease prognosis, early cancer diagnosis and pharmacodynamics. However, the extremely low abundance of CTCs limits their clinical utility because of technical challenges such as the isolation and subsequent detailed molecular and functional characterization of rare CTCs from patient blood samples. Methods: In this study, we present a novel density gradient centrifugation method employing biodegradable gelatin nanoparticles coated on silicon beads for the isolation, release, and downstream analysis of CTCs from colorectal and breast cancer patients. Results: Using clinical patient/spiked samples, we demonstrate that this method has significant CTC-capture efficiency (>80%) and purity (>85%), high CTC release efficiency (94%) and viability (92.5%). We also demonstrate the unparalleled robustness of our method in downstream CTC analyses such as the detection of PIK3CA mutations. Conclusion: The efficiency and versatility of the multifunctional density microbeads approach provides new opportunities for personalized cancer diagnostics and treatments.

Due to its unique advantages such as monodispersity and high throughput, droplet microfluidics has been widely used to generate diverse droplets/particles that have specific structures. Herein, we implemented Janus droplet parallel arrangements in a flow-focusing microchip through regulating corresponding fluid flow rates. Initially, fluorescence dye and PBS buffer solution kept laminar flow before the flow-focusing orifice and then was sheared into Janus droplets. Droplet diameter and corresponding generation frequency could be effectively manipulated. Subsequently, the generation of different Janus droplet parallel arrangements (e.g. monolayer, double-layer or three-layer arrangement) could be achieved by fluid regulation.

Circulating tumor cells (CTCs) have been believed to hold significant insights for cancer diagnosis and therapy. Here, we developed a simple and effective method to capture and release viable CTCs using core-shell Fe 3 O 4 @MnO 2 nanoparticles. Fe 3 O 4 @MnO 2 nanoparticles bioconjugated with anti-EpCAM antibody have characteristics of specific recognition, magnetic-driven cell isolation and oxalic acid-assisted cell release. The capture and release efficiency of target cancer cells were ∼83% and ∼55%, respectively. And ∼70% of released cells kept good viability, which could facilitate the subsequent cellular analysis.

Upconversion nanoparticles (UCNPs), with fascinating optical and chemical features, are a promising new generation of fluorescent probes. Although UCNPs have been widely used in diagnosis and therapy, there is an unmet need for a simple and effective surface engineering method that can produce cancer-targeting UCNPs. Here, we show that by coating particles with macrophage membranes, it becomes possible to utilize the adhesion between macrophages and cancer cells for effective cancer targeting. Natural macrophage membranes along with their associated membrane proteins were reconstructed into vesicles and then coated onto synthetic UCNPs. The resulting macrophage membrane-camouflaged particles (MM-UCNPs) exhibited effective cancer targeting capability inherited from the source cells and were further used for enhanced in vivo cancer imaging. Finally, the blood biochemistry, hematology testing and histology analysis results suggested a good in vivo biocompatibility of MM-UCNPs. The combination of synthetic nanoparticles with biomimetic cell membranes embodies a novel design strategy toward developing biocompatible nanoprobes for potential clinical applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 521-530, 2017.

In this paper, autofluorescent gelatin nanoparticles were synthesized as matrix metalloproteinase (MMP) responsive probes for cancer cell imaging. A modified two-step desolvation method was employed to generate these nanoparticles whose size was controllable and had stable autofluorescence. As glutaraldehyde was introduced as the crosslinking agent, the generation of Schiff base (CN) and double carbon bond (CC) between glutaraldehyde and gelatin endowed these gelatin nanoparticles distinct autofluorescence. Considering MMPs were usually overexpressed on the surface of cancer cells and they had degradation ability toward gelatin, we utilized these nanoparticles as imaging probes to responsively monitor the MMP metabolism of cancer cells according to the luminance change. As fluorescent probes, these nanoparticles had facile synthesis procedure and good biocompatibility, and provided a smart strategy to monitor cancer cell behaviors. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2854-2860, 2016.

Background: Capture and identification of circulating tumor cells (CTCs) in the blood system can help guide therapy and predict the prognosis of cancer patients. However, simultaneous capture and identification of CTCs with both epithelial and mesenchymal phenotypes remains a formidable technical challenge for cancer research. This study aimed at developing a system to efficiently capture and identify these CTCs with heterogeneous phenotypes using transparent nanomaterials and quantum dots (QDs)-based multiplexed imaging. Methods: Hydroxyapatite-chitosan (HA-CTS) nanofilm-coated substrates were modified based on our previous work to increase the capture efficiency of cancer cell lines by extending baking and incubating time. QDs-based imaging was applied to detect cytokeratin, epithelial cell adhesion molecule (EpCAM), and vimentin of cancer cells to demonstrate the feasibility of multiplexed imaging. And QDs-based multiplexed imaging of CD45, cytokeratin and vimentin was applied to detect CTCs from different cancer patients that were captured using HA-CTS nanofilm substrates. Results: Comparisons of the capture efficiencies of cancer cells at different baking time of film formation and incubating time of cell capture revealed the optimal baking and incubating time. Optimal time was chosen to develop a modified CTCs capture system that could capture EpCAM-positive cancer cells at an efficiency > 80%, and EpCAM-negative cancer cells at an efficiency > 50%. QDs-based imaging exhibited comparable detection ability but higher photostability compared to organic dyes imaging in staining cells. In addition, QDs-based multiplexed imaging also showed the molecular profiles of cancer cell lines with different phenotypes well. The integrated CTCs capture and identification system successfully captured and imaged CTCs with different sub-phenotypes in blood samples from cancer patients. Conclusion: This study demonstrated a reliable capture and detection system for heterogeneous CTCs that combined enrichment equipment based on HA-CTS nanofilm substrates with QDs-based multiplexed imaging.

As "liquid biopsies", circulating tumor cells (CTCs) have been thought to hold significant insights for cancer diagnosis and treatment. Despite the advances of microfluidic techniques that improve the capture of CTCs to a certain extent, recovering the captured CTCs with enhanced purity at the same time remains a challenge. Here, by combining on-chip purification and off-chip enzymatic treatment, we demonstrate a two-stage strategy to enhance the purity of captured cancer cells from blood samples. The on-chip purification introduces a stirring flow to increase the capture sensitivity and decrease nonspecifically bounded cells. The off-chip enzymatic treatment enables the cancer cells to be released from the attached magnetic beads, further improving the purity and enabling next reculture. For the proof-of-concept study, spiked cancer cells are successfully obtained from unprocessed whole blood with high recovery rate (∼68%) and purity (∼61%), facilitating subsequent RNA expression analysis.

In this work, a single-layer electric separator based on droplet microfluidics is demonstrated for cell sorting. We introduce a droplet pre-charging stratagem to reduce the voltages needed and increase droplet maneuverability. This stratagem and subsequent sorting process is implemented due to the effect of analogous uniform electric fields, which are generated by the 3D electrodes fabricated through injecting conductive silver paste into chambers in the PDMS layer. The mechanism of this droplet pre-charging process is experimentally verified and the amount of the inductive charges is quantitatively calculated. We also analyze the influence of the interaction between droplet size and channel walls on the manipulations of charge-carried droplets under certain electric fields. After parameter optimization, droplets with single cell encapsulated inside are separated out from other ones using this separator, and cell viability assay indicates that good cell status is maintained through the whole electric cascade.

We demonstrate the isolation of circulating tumor cells (CTCs) with a biocompatible nano-film composed of TiO2 nanoparticles. Due to the enhanced topographic interaction between nano-film and cancer cell surface, cancer cells (HCT116) spiked into PBS and healthy blood can be recovered from the suspension, whose efficiencies were respectively 80 % and 50 %. Benifit from the biocompatibility of this nano-film, in-situ culture of the captured cancer cells is also available, which provides an alternative selection when the capture cell number was inadequate or the sample cannot be analyzed immediately. For the proof-of-concept study, we use this nano-film to separate the circulating tumor cells from the colorectal and gastric cancer patient peripheral blood samples and the captured CTCs are identified by a three-colored immunocytochemistry method. We investigated the cancer cells capture strength at the nano-bio interface through exposing the cells to fluid shear stress in microfluidic device, which can be utilized to increase the purity of CTCs. The result indicated that 50 % of the captured cells can be detached from the substrate when the fluid shear stress was 180 dyn cm(-2). By integration of this CTCs capture nano-film with other single cell analysis device, we expected to further explore their applications in genome sequencing based on the captured CTCs.

Assays toward analysis of rare heterogeneous cells among identical specimen raise a significant challenge in many cell biological studies and clinical diagnosis applications. In this work, we report a disk-like hydrogel bead-based stratagem for rare cell researches at single cell level after a facile microfluidic-based particle synthesis approach. Cells of interested can be encapsulated into alginate droplets which are subsequently solidified into disk-like calcium alginate hydrogel beads and the bead size and cell number inside can be precisely controlled. Due to stability, permeability and disk-like shape of calcium alginate beads, cells immobilized in the disk-like beads can be treated with different chemicals with limited mechanical or fluidic operation influences and observed without distortion comparing with conventional methods or droplet microfluidic methods. Identification of circulating tumor cells, related to early-stage cancer diagnosis, is targeted to demonstrate the potential of our technique in rare cell analysis. This hydrogel bead-based stratagem is performed in immunofluorescence staining treatment and observation of cancer cells from normal hematological cells in blood sample. This method would have a great potential in single cell immobilization, manipulations and observation for biochemical cellular assays of rare cells.

In this paper, autofluorescent gelatin nanoparticles were synthesized as matrix metalloproteinase (MMP) responsive probes for cancer cell imaging. A modified two-step desolvation method was employed to generate these nanoparticles whose size was controllable and had stable autofluorescence. As glutaraldehyde was introduced as the crosslinking agent, the generation of Schiff base (CN) and double carbon bond (CC) between glutaraldehyde and gelatin endowed these gelatin nanoparticles distinct autofluorescence. Considering MMPs were usually overexpressed on the surface of cancer cells and they had degradation ability toward gelatin, we utilized these nanoparticles as imaging probes to responsively monitor the MMP metabolism of cancer cells according to the luminance change. As fluorescent probes, these nanoparticles had facile synthesis procedure and good biocompatibility, and provided a smart strategy to monitor cancer cell behaviors. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2854-2860, 2016.

In this work, we developed a shape-controllable nozzle inside a multilayer PDMS microchip. The nozzle was able to control the shape of the fluid channel in three dimensions. All the four walls of the fluid channel were comprised of pneumatic PDMS membrane valves, and their deformation was controlled by air pressure. As both the limitation of the fluid flux and the shape of the fluid channel were adjustable spatially in three dimensions, this valve-based nozzle generated droplets with less response time and in a more effectively controlled manner comparing to conventional droplet devices. It could also function as a microinjector to modulate the compositions of droplets precisely and continuously. In addition, the nozzle was able to form a specific shape to generate core–shell particles.

Microfluidics-based circulating tumor cell (CTC) isolation is achieved by using gelatin-coated silica microbeads conjugated to CTC-specific antibodies. Bead-binding selectively enlarges target cell size, providing efficient high-purity capture. CTCs captured can be further released non-invasively. This stratagem enables high-performance CTC isolation for subsequent studies.

Non-invasive prenatal diagnostics (NIPD) has been an emerging field for prenatal diagnosis research. Carrying the whole genome coding of the fetus, fetal nucleated red blood cells (FNRBCs) have been pursued as a surrogate biomarker traveling around in maternal blood. Here, by combining a unique microbead-based centrifugal separation and enzymatic release, we demonstrated a novel method for FNRBC isolation from the blood samples. First, the gelatin-coated silica microbeads were modified with FNRBC-specific antibody (anti-CD147) to capture the target cells in the blood samples. Then, the density difference between microbead-bound FNRBCs and normal blood cells enables the purification of FNRBCs via an improved high-density percoll-based separation. The non-invasive release of FNRBCs can then be achieved by enzymatically degrading the gelatin film on the surface of the microbeads, allowing a gentle release of the captured target cells with as high as 84% efficiency and ∼80% purity. We further applied it to isolate fetal cells from maternal peripheral blood. The released cells were analyzed by real-time polymerase chain reaction to verify their fetal origin and fluorescent in situ hybridization to detect fetal chromosome disorders. This straightforward and reliable alternative platform for FNRBC detection may have the potential for realizing facile NIPD.

For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have reported a phenomenon known as "accelerated blood clearance (ABC)" where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane-coated Fe(3)O(4) nanoparticles (Fe(3)O(4) @RBC NPs) rely on CD47, which is a "don't eat me" marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein-alpha (SIRP-α) receptor. Fe(3)O(4) @RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe(3)O(4) @RBC NPs does not elicit immune responses on neither the cellular level (myeloid-derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane-camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long-existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.

A CTCs detection assay using transparent MnO2 nanospheres thin films to capture and release of CTCs is reported. The enhanced local topography interaction between extracellular matrix scaffolds and the antibody-coated substrate leads to improved capture efficiency. CTCs captured from artificial blood sample can be cultured and released, represent a new functional material capable of CTCs isolation and culture for subsequent studies.

This paper introduces a cancer cell capture/release microchip based on the self-sacrificed MnO2 nanofibers. Through electrospinning, lift-off and soft-lithography procedures, MnO2 nanofibers are tactfully fabricated in microchannels to implement enrichment and release of cancer cells in liquid samples. The MnO2 nanofiber net which mimics the extra cellular matrix can lead to high capture ability with the help of a cancer cell-specific antibody bio-conjugation. Subsequently, an effective and friendly release method is carried out by using low concentration of oxalic acid to dissolve the MnO2 nanofiber substrate while keeping high viability of those released cancer cells at the same time. It is conceivable that our microchip may have potentials in realizing biomedical analysis of circulating tumor cells for biological and clinical researches in oncology.