Nanotentacle‐Structured Magnetic Particles for Efficient Capture of Circulating Tumor Cells

Circulating tumor cells (CTCs) have attracted considerable attention as promising markers for diagnosing and monitoring the cancer status. Despite many technological advances in isolating CTCs, the capture efficiency and purity still remain challenges that limit clinical practice. Here, the construction of “nanotentacle”‐structured magnetic particles using M13‐bacteriophage and their application for the efficient capturing of CTCs is demonstrated. The M13‐bacteriophage to magnetic particles followed by modification with PEG is conjugated, and further tethered monoclonal antibodies against the epidermal receptor 2 (HER2). The use of nanotentacle‐structured magnetic particles results in a high capture purity (>45%) and efficiency (>90%), even for a smaller number of cancer cells (≈25 cells) in whole blood. Furthermore, the cancer cells captured are shown to maintain a viability of greater than 84%. The approach can be effectively used for capturing CTCs with high efficiency and purity for the diagnosis and monitoring of cancer status.     

Efficient Capture and Simple Quantification of Circulating Tumor Cells Using Quantum Dots and Magnetic Beads

Circulating tumor cells (CTCs) are valuable biomarkers for monitoring the status of cancer patients and drug efficacy. However, the number of CTCs in the blood is extremely low, and the isolation and detection of CTCs with high efficiency and sensitivity remain a challenge. Here, we present an approach to the efficient capturing and simple quantification of CTCs using quantum dots and magnetic beads. Anti‐EpCAM antibody‐conjugated quantum dots are used for the targeting and quantification of CTCs, and quantum‐dot‐attached CTCs are isolated using anti‐IgG‐modified magnetic beads. Our approach is shown to result in a capture efficiency of about 70%–80%, enabling the simple quantification of captured CTCs based on the fluorescence intensity of the quantum dots. The present method can be used effectively in the capturing and simple quantification of CTCs with high efficiency for cancer diagnosis and monitoring.     

Leukocyte‐Repelling Biomimetic Immunomagnetic Nanoplatform for High‐Performance Circulating Tumor Cells Isolation

Downstream studies of circulating tumor cells (CTCs), which may provide indicative evaluation information for therapeutic efficacy, cancer metastases, and cancer prognosis, are seriously hindered by the poor purity of enriched CTCs as large amounts of interfering leukocytes still nonspecifically bind to the isolation platform. In this work, biomimetic immunomagnetic nanoparticles (BIMNs) with the following features are designed: i) the leukocyte membrane camouflage, which could greatly reduce homologous leukocyte interaction and actualize high‐purity CTCs isolation, is easily extracted by graphene nanosheets; ii) facile antibody conjugation can be achieved through the “insertion” of biotinylated lipid molecules into leukocyte‐membrane‐coated nanoparticles and streptavidin conjunction; iii) layer‐by‐layer assembly techniques could integrate high‐magnetization Fe₃O₄ nanoparticles and graphene nanosheets efficiently. Consequently, the resulting BIMNs achieve a capture efficiency above 85.0% and CTCs purity higher than 94.4% from 1 mL blood with 20–200 CTCs after 2 min incubation. Besides, 98.0% of the isolated CTCs remain viable and can be directly cultured in vitro. Moreover, application of the BIMNs to cancer patients' peripheral blood shows good reproducibility (mean relative standard deviation 8.7 ± 5.6%). All results above suggest that the novel biomimetic nanoplatform may serve as a promising tool for CTCs enrichment and detection from clinical samples.     

Capturing Cancer: Emerging Microfluidic Technologies for the Capture and Characterization of Circulating Tumor Cells

Circulating tumor cells (CTCs) escape from primary or metastatic lesions and enter into circulation, carrying significant information of cancer progression and metastasis. Capture of CTCs from the bloodstream and the characterization of these cells hold great significance for the detection, characterization, and monitoring of cancer. Despite the urgent need from clinics, it remains a major challenge to capture and retain these rare cells from human blood with high specificity and yield. Recent exciting advances in micro/nanotechnology, microfluidics, and materials science have enable versatile, robust, and efficient cell isolation and processing through the development of new micro/nanoengineered devices and biomaterials. This review provides a summary of recent progress along this direction, with a focus on emerging methods for CTC capture and processing, and their application in cancer research. Furthermore, classical as well as emerging cellular characterization methods are reviewed to reveal the role of CTCs in cancer progression and metastasis, and hypotheses are proposed in regard to the potential emerging research directions most desired in CTC‐related cancer research.     

Continuous Flow Deformability‐Based Separation of Circulating Tumor Cells Using Microfluidic Ratchets

Circulating tumor cells (CTCs) offer tremendous potential for the detection and characterization of cancer. A key challenge for their isolation and subsequent analysis is the extreme rarity of these cells in circulation. Here, a novel label‐free method is described to enrich viable CTCs directly from whole blood based on their distinct deformability relative to hematological cells. This mechanism leverages the deformation of single cells through tapered micrometer scale constrictions using oscillatory flow in order to generate a ratcheting effect that produces distinct flow paths for CTCs, leukocytes, and erythrocytes. A label‐free separation of circulating tumor cells from whole blood is demonstrated, where target cells can be separated from background cells based on deformability despite their nearly identical size. In doping experiments, this microfluidic device is able to capture >90% of cancer cells from unprocessed whole blood to achieve 10⁴‐fold enrichment of target cells relative to leukocytes. In patients with metastatic castration‐resistant prostate cancer, where CTCs are not significantly larger than leukocytes, CTCs can be captured based on deformability at 25× greater yield than with the conventional CellSearch system. Finally, the CTCs separated using this approach are collected in suspension and are available for downstream molecular characterization.     

Fast and Highly Sensitive Ionic‐Polymer‐Gated WS2–Graphene Photodetectors

The combination of graphene with semiconductor materials in heterostructure photodetectors enables amplified detection of femtowatt light signals using micrometer‐scale electronic devices. Presently, long‐lived charge traps limit the speed of such detectors, and impractical strategies, e.g., the use of large gate‐voltage pulses, have been employed to achieve bandwidths suitable for applications such as video‐frame‐rate imaging. Here, atomically thin graphene–WS₂ heterostructure photodetectors encapsulated in an ionic polymer are reported, which are uniquely able to operate at bandwidths up to 1.5 kHz whilst maintaining internal gain as large as 10⁶. Highly mobile ions and the nanometer‐scale Debye length of the ionic polymer are used to screen charge traps and tune the Fermi level of the graphene over an unprecedented range at the interface with WS₂. Responsivity R = 10⁶ A W^?1 and detectivity D* = 3.8 × 10¹¹ Jones are observed, approaching that of single‐photon counters. The combination of both high responsivity and fast response times makes these photodetectors suitable for video‐frame‐rate imaging applications.     

Enhanced and Differential Capture of Circulating Tumor Cells from Lung Cancer Patients by Microfluidic Assays Using Aptamer Cocktail

Collecting circulating tumor cells (CTCs) shed from solid tumor through a minimally invasive approach provides an opportunity to solve a long‐standing oncology problem, the real‐time monitoring of tumor state and analysis of tumor heterogeneity. However, efficient capture and detection of CTCs with diverse phenotypes is still challenging. In this work, a microfluidic assay is developed using the rationally‐designed aptamer cocktails with synergistic effect. Enhanced and differential capture of CTCs for nonsmall cell lung cancer (NSCLC) patients is achieved. It is also demonstrated that the overall consideration of CTC counts obtained by multiple aptamer combinations can provide more comprehensive information in treatment monitoring.     

A Trachea‐Inspired Bifurcated Microfilter Capturing Viable Circulating Tumor Cells via Altered Biophysical Properties as Measured by Atomic Force Microscopy

Circulating tumor cells (CTCs), though exceedingly rare in the blood, are nonetheless becoming increasingly important in cancer diagnostics. Despite this keen interest and the growing number of potential clinical applications, there has been limited success in developing a CTC isolation platform that simultaneously optimizes recovery rates, purity, and cell compatibility. Herein, a novel tracheal carina‐inspired bifurcated (TRAB) microfilter system is reported, which uses an optimal filter gap size satisfying both 100% theoretical recovery rate and purity, as determined by biomechanical analysis and fluid–structure interaction (FSI) simulations. Biomechanical properties are also used to clearly discriminate between cancer cells and leukocytes, whereby cancer cells are selectively bound to melamine microbeads, which increase the size and stiffness of these cells. Nanoindentation experiments are conducted to measure the stiffness of leukocytes as compared to the microbead‐conjugated cancer cells, with these parameters then being used in FSI analyses to optimize the filter gap size. The simulation results show that given a flow rate of 100 μL min^?1, an 8 μm filter gap optimizes the recovery rate and purity. MCF‐7 breast cancer cells with solid microbeads are spiked into 3 mL of whole blood and, by using this flow rate along with the optimized microfilter dimensions, the cell mixture passes through the TRAB filter, which achieves a recovery rate of 93% and purity of 59%. Regarding cell compatibility, it is verified that the isolation procedure does not adversely affect cell viability, thus also confirming that the re‐collected cancer cells can be cultured for up to 8 days. This work demonstrates a CTC isolation technology platform that optimizes high recovery rates and cell purity while also providing a framework for functional cell studies, potentially enabling even more sensitive and specific cancer diagnostics.     

Antibody‐Free Hydrogel with the Synergistic Effect of Cell Imprinting and Boronate Affinity: Toward the Selective Capture and Release of Undamaged Circulating Tumor Cells

The selective and highly efficient capture of circulating tumor cells (CTCs) from blood and their subsequent release without damage are very important for the early diagnosis of tumors and for understanding the mechanism of metastasis. Herein, a universal strategy is proposed for the fabrication of an antibody‐free hydrogel that has a synergistic effect by featuring microinterfaces obtained by cell imprinting and molecular recognition conferred by boronate affinity. With this artificial antibody, highly efficient capture of human hepatocarcinoma SMMC‐7721 cells is achieved: as many as 90.3 ± 1.4% (n = 3) cells are captured when 1 × 10⁵ SMMC‐7721 cells are incubated on a 4.5 cm² hydrogel, and 99% of these captured cells are subsequently released without any loss of proliferation ability. In the presence of 1000 times as many nontarget cells, namely, leukaemia Jurkat cells, the SMMC‐7721 cells can be captured with an enrichment factor as high as 13.5 ± 3.2 (n = 3), demonstrating the superior selectivity of the artificial antibody for the capture of the targeted CTCs. Most importantly, the SMMC‐7721 cells can be successfully captured even when spiked into whole blood, indicating the great promise of this approach for the further molecular characterization of CTCs.     

A Radial Flow Microfluidic Device for Ultra‐High‐Throughput Affinity‐Based Isolation of Circulating Tumor Cells

Circulating tumor cells (CTCs) are believed to play an important role in metastasis, a process responsible for the majority of cancer‐related deaths. But their rarity in the bloodstream makes microfluidic isolation complex and time‐consuming. Additionally the low processing speeds can be a hindrance to obtaining higher yields of CTCs, limiting their potential use as biomarkers for early diagnosis. Here, a high throughput microfluidic technology, the OncoBean Chip, is reported. It employs radial flow that introduces a varying shear profile across the device, enabling efficient cell capture by affinity at high flow rates. The recovery from whole blood is validated with cancer cell lines H1650 and MCF7, achieving a mean efficiency >80% at a throughput of 10 mL h^?1 in contrast to a flow rate of 1 mL h^?1 standardly reported with other microfluidic devices. Cells are recovered with a viability rate of 93% at these high speeds, increasing the ability to use captured CTCs for downstream analysis. Broad clinical application is demonstrated using comparable flow rates from blood specimens obtained from breast, pancreatic, and lung cancer patients. Comparable CTC numbers are recovered in all the samples at the two flow rates, demonstrating the ability of the technology to perform at high throughputs.     

Graphene Oxide,Highly Reduced Graphene Oxide,and Graphene: Versatile Building Blocks for Carbon‐Based Materials

Isolated graphene, a nanometer‐thick two‐dimensional analog of fullerenes and carbon nanotubes, has recently sparked great excitement in the scientific community given its excellent mechanical and electronic properties. Particularly attractive is the availability of bulk quantities of graphene as both colloidal dispersions and powders, which enables the facile fabrication of many carbon‐based materials. The fact that such large amounts of graphene are most easily produced via the reduction of graphene oxide—oxygenated graphene sheets covered with epoxy, hydroxyl, and carboxyl groups—offers tremendous opportunities for access to functionalized graphene‐based materials. Both graphene oxide and graphene can be processed into a wide variety of novel materials with distinctly different morphological features, where the carbonaceous nanosheets can serve as either the sole component, as in papers and thin films, or as fillers in polymer and/or inorganic nanocomposites. This Review summarizes techniques for preparing such advanced materials via stable graphene oxide, highly reduced graphene oxide, and graphene dispersions in aqueous and organic media. The excellent mechanical and electronic properties of the resulting materials are highlighted with a forward outlook on their applications.