Microfluidics for label-free sorting of rare circulating tumor cells

Zhu, Shu; Jiang, Fan; Han, Yu; Xiang, Nan; Zhang, Ni

doi:10.1039/d0an01148g

Cited by 62 publications

(46 citation statements)

References 177 publications

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“…Most of the available immune-based microfluidic systems utilize positive selection of CTCs, and rely on epithelial cell adhesion molecule, EpCAM, a transmembrane glycoprotein, expression. EpCAM is a surface marker commonly used to detect CTCs, since it is present in tumor cells derived from human epithelial tumors, but absent in blood cells [ 70 , 73 ]. CTC-chip, a microfluidic device for CTCs detection containing microposts coated with antibodies against EpCAM molecule was first introduced by Nagrath et al The chip detected CTCs in 115 of 116 (99%) samples from patients with metastatic breast, colon, lung, prostate, and pancreatic cancer with 50% purity and a range of 5–1281 CTCs per sample ml of blood [ 74 ].…”

Section: Lab-on-a-chip Approaches For Liquid Biopsiesmentioning

confidence: 99%

Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Carvalho

Ferreira

Seixas

et al. 2021

Cancers

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Despite the intensive efforts dedicated to cancer diagnosis and treatment, lung cancer (LCa) remains the leading cause of cancer-related mortality, worldwide. The poor survival rate among lung cancer patients commonly results from diagnosis at late-stage, limitations in characterizing tumor heterogeneity and the lack of non-invasive tools for detection of residual disease and early recurrence. Henceforth, research on liquid biopsies has been increasingly devoted to overcoming these major limitations and improving management of LCa patients. Liquid biopsy is an emerging field that has evolved significantly in recent years due its minimally invasive nature and potential to assess various disease biomarkers. Several strategies for characterization of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been developed. With the aim of standardizing diagnostic and follow-up practices, microfluidic devices have been introduced to improve biomarkers isolation efficiency and specificity. Nonetheless, implementation of lab-on-a-chip platforms in clinical practice may face some challenges, considering its recent application to liquid biopsies. In this review, recent advances and strategies for the use of liquid biopsies in LCa management are discussed, focusing on high-throughput microfluidic devices applied for CTCs and ctDNA isolation and detection, current clinical validation studies and potential clinical utility.

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Section: Lab-on-a-chip Approaches For Liquid Biopsiesmentioning

confidence: 99%

Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Carvalho

Ferreira

Seixas

et al. 2021

Cancers

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“…To this end, inertial microfluidics is attractive since the active and passive, sizebased, technology exploits inherent surface property and hydrodynamic forces that scale with increased flow rate and among them spiral channel designs have been shown to operate at extremely high volumetric flow rates (∼mL/min) [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. However, microfluidic technology has been utilized extensively to precisely focus and separate mammalian cells, including circulating tumor cells [34][35][36][37][38][39][40][41][42][43][44][45][46], but the separation of small-sized bacteria from blood has been challenging. The main challenge in inertial microfluidics-based bacteria separation is due to the narrow size difference between bacteria (∼1-2 μm) and blood cells (∼3-15 μm).…”

Section: Introductionmentioning

confidence: 99%

High resolution and rapid separation of bacteria from blood using elasto‐inertial microfluidics

et al. 2021

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Improved sample preparation has the potential to address unmet needs for fast turnaround sepsis tests. In this work, we report elasto-inertial based rapid bacteria separation from diluted blood at high separation efficiency. In viscoelastic flows, we demonstrate novel findings where blood cells prepositioned at the outer wall entering a spiral device remain fully focused throughout the channel length while smaller bacteria migrate to the opposite wall. Initially, using microparticles, we show that particles above a certain size cut-off remain fully focused at the outer wall while smaller particles differentially migrate toward the inner wall. We demonstrate particle separation at 1 μm resolution at a total throughput of 1 mL/min. For blood-based experiments, a minimum of 1:2 dilution was necessary to fully focus blood cells at the outer wall. Finally, Escherichia coli spiked in diluted blood were continuously separated at a total flow rate of 1 mL/min, with efficiencies between 82 and 90% depending on the blood dilution. Using a single spiral, it takes 40 min to process 1 mL of blood at a separation efficiency of 82%. The label-free, passive, and rapid bacteria isolation method has a great potential for speeding up downstream phenotypic and genotypic analysis.

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“…Researchers have found that there are differences in the biological and physical characteristics between CTCs and blood cells (e.g., biomarkers, size, density, and deformability) ( Ferreira et al, 2016 ). Based on these properties, immunomagnetic bead capture ( Markou et al, 2011 ; Chang et al, 2020 ; Wu et al, 2020 ), filtering systems ( Chang et al, 2015 ; Yoshino et al, 2016 ; Xia et al, 2018 ), and microfluidics ( Patil et al, 2015 ; Abdulla et al, 2020 ; Zhu et al, 2020 ) have been developed to isolate CTCs. The CellSearch system, which utilizes immunomagnetic beads coupled with antibodies to identify and isolate CTCs under the effect of external magnetic fields ( Riethdorf et al, 2007 ), has good specificity, and the principle is simple.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Separation Efficiency and Purity of Circulating Tumor Cells Based on the Combined Effects of Double Sheath Fluids and Inertial Focusing

Liu

Sun

et al. 2021

Front. Bioeng. Biotechnol.

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Circulating tumor cells (CTCs) play a crucial role in solid tumor metastasis, but obtaining high purity and viability CTCs is a challenging task due to their rarity. Although various works using spiral microchannels to isolate CTCs have been reported, the sorting purity of CTCs has not been significantly improved. Herein, we developed a novel double spiral microchannel for efficient separation and enrichment of intact and high-purity CTCs based on the combined effects of two-stage inertial focusing and particle deflection. Particle deflection relies on the second sheath to produce a deflection of the focused sample flow segment at the end of the first-stage microchannel, allowing larger particles to remain focused and entered the second-stage microchannel while smaller particles moved into the first waste channel. The deflection of the focused sample flow segment was visualized. Testing by a binary mixture of 10.4 and 16.5 μm fluorescent microspheres, it showed 16.5 μm with separation efficiency of 98% and purity of 90% under the second sheath flow rate of 700 μl min−1. In biological experiments, the average purity of spiked CTCs was 74% at a high throughput of 1.5 × 108 cells min−1, and the recovery was more than 91%. Compared to the control group, the viability of separated cells was 99%. Finally, we validated the performance of the double spiral microchannel using clinical cancer blood samples. CTCs with a concentration of 2–28 counts ml−1 were separated from all 12 patients’ peripheral blood. Thus, our device could be a robust and label-free liquid biopsy platform in inertial microfluidics for successful application in clinical trials.

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Microfluidics for label-free sorting of rare circulating tumor cells

Abstract: Circulating tumor cells (CTCs) have been widely considered as promising novel biomarkers for molecular research and clinical diagnosis of cancer. However, the sorting of CTCs is very challenging due to...

Cited by 62 publications

References 177 publications

Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

High resolution and rapid separation of bacteria from blood using elasto‐inertial microfluidics

Enhanced Separation Efficiency and Purity of Circulating Tumor Cells Based on the Combined Effects of Double Sheath Fluids and Inertial Focusing

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