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Ashok D, Singh J, Howard HR, Cottam S, Waterhouse A, Bilek MMM. Interfacial engineering for biomolecule immobilisation in microfluidic devices. Biomaterials 2025; 316:123014. [PMID: 39708778 DOI: 10.1016/j.biomaterials.2024.123014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/25/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024]
Abstract
Microfluidic devices are used for various applications in biology and medicine. From on-chip modelling of human organs for drug screening and fast and straightforward point-of-care (POC) detection of diseases to sensitive biochemical analysis, these devices can be custom-engineered using low-cost techniques. The microchannel interface is essential for these applications, as it is the interface of immobilised biomolecules that promote cell capture, attachment and proliferation, sense analytes and metabolites or provide enzymatic reaction readouts. However, common microfluidic materials do not facilitate the stable immobilisation of biomolecules required for relevant applications, making interfacial engineering necessary to attach biomolecules to the microfluidic surfaces. Interfacial engineering is performed through various immobilisation mechanisms and surface treatment techniques, which suitably modify the surface properties like chemistry and energy to obtain robust biomolecule immobilisation and long-term storage stability suitable for the final application. In this review, we provide an overview of the status of interfacial engineering in microfluidic devices, covering applications, the role of biomolecules, their immobilisation pathways and the influence of microfluidic materials. We then propose treatment techniques to optimise performance for various biological and medical applications and highlight future areas of development.
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Affiliation(s)
- Deepu Ashok
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; Heart Research Institute, Newtown, NSW, 2042, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia; School of Physics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Jasneil Singh
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; Heart Research Institute, Newtown, NSW, 2042, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Henry Robert Howard
- The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Sophie Cottam
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia; School of Physics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Anna Waterhouse
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.
| | - Marcela M M Bilek
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia; School of Physics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia.
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Mansor M, Yang C, Chong KL, Jamrus MA, Liu K, Yu M, Ahmad MR, Ren X. Label-Free and Rapid Microfluidic Design Rules for Circulating Tumor Cell Enrichment and Isolation: A Review and Simulation Analysis. ACS OMEGA 2025; 10:6306-6322. [PMID: 40028152 PMCID: PMC11866005 DOI: 10.1021/acsomega.4c08606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 03/05/2025]
Abstract
Enriching and isolating circulating tumor cells (CTCs) have attracted significant interest due to their important role in early cancer diagnosis and prognosis, allowing for minimally invasive approaches and providing vital information about metastasis at the cellular level. This review comprehensively summarizes the recent developments in microfluidic devices for CTC enrichment and isolation. The advantages and limitations of several microfluidic devices are discussed, and the design specifications of microfluidic devices for CTC enrichment are highlighted. We also developed a set of methodologies and design rules of label-free microfluidics such as spiral, deterministic lateral displacement (DLD) and dielectrophoresis (DEP) to allow researchers to design and develop microfluidic devices systematically and effectively, promoting rapid research on design, fabrication, and experimentation.
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Affiliation(s)
- Muhammad
Asraf Mansor
- Department
of Control and Mechatronics Engineering, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia
| | - Chun Yang
- School
of Microelectronics, Tianjin University, Tianjin 300072, China
| | - Kar Lok Chong
- Department
of Control and Mechatronics Engineering, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia
| | - Muhammad Asyraf Jamrus
- Department
of Control and Mechatronics Engineering, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia
| | - Kewei Liu
- Sino-German
College of Intelligent Manufacturing, Shenzhen
Technology University, Shenzhen 518118, China
| | - Miao Yu
- Department
of Research and Development, Stedical Scientific, Carlsbad, California 92010, United States
| | - Mohd Ridzuan Ahmad
- Department
of Control and Mechatronics Engineering, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia
| | - Xiang Ren
- School
of Microelectronics, Tianjin University, Tianjin 300072, China
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3
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Abusamra SM, Barber R, Sharafeldin M, Edwards CM, Davis JJ. The integrated on-chip isolation and detection of circulating tumour cells. SENSORS & DIAGNOSTICS 2024; 3:562-584. [PMID: 38646187 PMCID: PMC11025039 DOI: 10.1039/d3sd00302g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/12/2024] [Indexed: 04/23/2024]
Abstract
Circulating tumour cells (CTCs) are cancer cells shed from a primary tumour which intravasate into the blood stream and have the potential to extravasate into distant tissues, seeding metastatic lesions. As such, they can offer important insight into cancer progression with their presence generally associated with a poor prognosis. The detection and enumeration of CTCs is, therefore, critical to guiding clinical decisions during treatment and providing information on disease state. CTC isolation has been investigated using a plethora of methodologies, of which immunomagnetic capture and microfluidic size-based filtration are the most impactful to date. However, the isolation and detection of CTCs from whole blood comes with many technical barriers, such as those presented by the phenotypic heterogeneity of cell surface markers, with morphological similarity to healthy blood cells, and their low relative abundance (∼1 CTC/1 billion blood cells). At present, the majority of reported methods dissociate CTC isolation from detection, a workflow which undoubtedly contributes to loss from an already sparse population. This review focuses on developments wherein isolation and detection have been integrated into a single-step, microfluidic configuration, reducing CTC loss, increasing throughput, and enabling an on-chip CTC analysis with minimal operator intervention. Particular attention is given to immune-affinity, microfluidic CTC isolation, coupled to optical, physical, and electrochemical CTC detection (quantitative or otherwise).
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Affiliation(s)
- Sophia M Abusamra
- Nuffield Department of Surgical Sciences, University of Oxford Oxford OX3 9DU UK
| | - Robert Barber
- Department of Chemistry, University of Oxford Oxford OX1 3QZ UK
| | | | - Claire M Edwards
- Nuffield Department of Surgical Sciences, University of Oxford Oxford OX3 9DU UK
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Systems, University of Oxford Oxford UK
| | - Jason J Davis
- Department of Chemistry, University of Oxford Oxford OX1 3QZ UK
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4
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Jayan H, Yin L, Xue S, Zou X, Guo Z. Raman spectroscopy-based microfluidic platforms: A promising tool for detection of foodborne pathogens in food products. Food Res Int 2024; 180:114052. [PMID: 38395567 DOI: 10.1016/j.foodres.2024.114052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/15/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024]
Abstract
Rapid and sensitive detection of foodborne pathogens in food products is paramount for ensuring food safety and public health. In the ongoing effort to tackle this issue, detection methods are continually researched and upgraded to achieve rapidity, sensitivity, portability, and cost-effectiveness. This review addresses the critical need for improved technique by focusing on Raman spectroscopy-based microfluidic platforms, which have shown potential in revolutionizing the field of foodborne pathogen analysis offering point-of-care diagnosis and multiplex detection. The key problem lies in the persistent threat of compromised food quality and public health due to inadequate pathogen detection. The review elucidates the various trapping strategies employed in a microfluidic platform, including optical trapping, electrical trapping, mechanical trapping, and acoustic trapping for the capture of microbial cells. Subsequently, the review delves into the key aspects of the application of microbial detection in food products, highlighting recent advances and challenges in the field. The integrated technique allows point-of-care application assessment, which is an attractive quality for in-line and real-time detection of foodborne pathogens. However, the application of the technique in food products is limited and requires further research to combat the complexity of the food matrix, reduced costs of production, and ensure real-time use for diverse pathogens. Ultimately, this review aims to propel advancements in microbial detection, thus promoting enhanced food safety through state-of-the-art technologies.
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Affiliation(s)
- Heera Jayan
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing, Jiangsu University, Zhenjiang 212013, China
| | - Limei Yin
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Shanshan Xue
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Xiaobo Zou
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing, Jiangsu University, Zhenjiang 212013, China
| | - Zhiming Guo
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; China Light Industry Key Laboratory of Food Intelligent Detection & Processing, Jiangsu University, Zhenjiang 212013, China.
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Macaraniag C, Zhou J, Li J, Putzbach W, Hay N, Papautsky I. Microfluidic isolation of breast cancer circulating tumor cells from microvolumes of mouse blood. Electrophoresis 2023; 44:1859-1867. [PMID: 37528726 DOI: 10.1002/elps.202300108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/30/2023] [Accepted: 07/10/2023] [Indexed: 08/03/2023]
Abstract
Liquid biopsy has shown significant research and clinical implications in cancer. Particularly, the isolation of circulating tumor cells (CTCs) in preclinical studies can provide crucial information about disease progression and therefore may guide treatment decisions. Microfluidic isolation systems have played a considerable role in CTC isolation for cancer studies, disease diagnosis, and prognosis. CTCs are often studied using preclinical animal models such as xenografts or syngeneic models. However, most isolation systems are tested on human cell lines and human blood, whereas less validation studies are done on preclinical samples such as CTCs from mouse models. Here, we demonstrate and evaluate a complete workflow of a sized-based inertial microfluidic device to isolate CTCs from blood using exclusively mouse blood and mouse cancer cell lines. We then incorporate the cytospin, a commonly used method for enumeration of small number of cells in a glass slide to quantify the total cell yield of our workflow.
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Affiliation(s)
- Celine Macaraniag
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, Illinois, USA
| | - Jian Zhou
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, Illinois, USA
- University of Illinois Cancer Center, Chicago, Illinois, USA
| | - Jing Li
- Department of Biochemistry and Molecular Genetics, University of Illinois Chicago, Chicago, Illinois, USA
| | - William Putzbach
- Department of Biochemistry and Molecular Genetics, University of Illinois Chicago, Chicago, Illinois, USA
| | - Nissim Hay
- University of Illinois Cancer Center, Chicago, Illinois, USA
- Department of Biochemistry and Molecular Genetics, University of Illinois Chicago, Chicago, Illinois, USA
| | - Ian Papautsky
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, Illinois, USA
- University of Illinois Cancer Center, Chicago, Illinois, USA
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Li G, Ji Y, Wu Y, Liu Y, Li H, Wang Y, Chi M, Sun H, Zhu H. Multistage microfluidic cell sorting method and chip based on size and stiffness. Biosens Bioelectron 2023; 237:115451. [PMID: 37327603 DOI: 10.1016/j.bios.2023.115451] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/13/2023] [Accepted: 06/05/2023] [Indexed: 06/18/2023]
Abstract
High performance sorting of circulating tumor cells (CTCs) from peripheral blood is key to liquid biopsies. Size-based deterministic lateral displacement (DLD) technique is widely used in cell sorting. But conventional microcolumns have poor fluid regulation ability, which limits the sorting performance of DLD. When the size difference between CTCs and leukocytes is small (e.g., less than 3 μm), not only DLD, many size-based separation techniques fail due to low specificity. CTCs have been confirmed to be softer than leukocytes, which could serve as a basis for sorting. In this study, we presented a multistage microfluidic CTCs sorting method, first sorting CTCs using a size-based two-array DLD chip, then purifying CTCs mixed by leukocytes using a stiffness-based cone channel chip, and finally identifying cell types using Raman techniques. The entire CTCs sorting and analysis process was label free, highly pure, high-throughput and efficient. The two-array DLD chip employed a droplet-shaped microcolumn (DMC) developed by optimization design rather than empirical design. Attributed to the excellent fluid regulation capability of DMC, the CTCs sorter system developed by parallelizing four DMC two-array DLD chips was able to process a sample of 2.5 mL per minute with a recovery efficiency of 96.30 ± 2.10% and a purity of 98.25 ± 2.48%. To isolate CTCs mixed dimensionally by leukocytes, a cone channel sorting method and chip were developed based on solid and hydrodynamic coupled analysis. The cone channel chip allowed CTCs to pass through the channel and entrap leukocytes, improving the purity of CTCs mixed by leukocytes by 1.8-fold.
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Affiliation(s)
- Gaolin Li
- Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), Chinese Academy of Sciences, Changchun, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yuan Ji
- Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), Chinese Academy of Sciences, Changchun, China
| | - Yihui Wu
- Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), Chinese Academy of Sciences, Changchun, China.
| | - Yongshun Liu
- Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), Chinese Academy of Sciences, Changchun, China
| | - Huan Li
- Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), Chinese Academy of Sciences, Changchun, China.
| | - Yimeng Wang
- Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), Chinese Academy of Sciences, Changchun, China; University of Chinese Academy of Sciences, Beijing, China
| | - Mingbo Chi
- Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), Chinese Academy of Sciences, Changchun, China
| | - Hongyan Sun
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, China
| | - Hongquan Zhu
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, China
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7
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Bai S, Lin S, Lin T, Wang Q, Cheng C, Lin J, Zhang Y, Jiang X, Han X. Clinical diagnostic biomarker "circulating tumor cells" in breast cancer - a meta-analysis. Front Oncol 2023; 13:1137519. [PMID: 37397397 PMCID: PMC10313226 DOI: 10.3389/fonc.2023.1137519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/31/2023] [Indexed: 07/04/2023] Open
Abstract
Objective Using meta-analysis, we evaluate circulating tumor cells(CTCs) as a potential diagnostic tool for breast cancer. Methods A document search was conducted using publicly available databases up to May 2021. Specific inclusion and exclusion criteria were formulated and summarize relevant data through literature types, research types, case populations, samples, etc. Subgroup analysis of documents based on regions, enrichment methods, and detection methods. The included research projects were evaluated using DeeKs' bias, and evaluation indicators such as specificity (SPE), sensitivity (SEN), diagnosis odds ratio (DOR) were used as evaluation indicators. Results 16 studies on the use of circulating tumor cells to diagnose breast cancer were included in our meta-analysis. Overall sensitivity value was 0.50 (95%CI:0.48-0.52), specificity value was 0.93 (95%CI:0.92- 0.95), DOR value was 33.41 (95%CI:12.47-89.51), and AUC value was 0.8129. Conclusion In meta-regressions and subgroup analysis, potential heterogeneity factors were analyzed, but the source of heterogeneity is still unclear. CTCs, as a novel tumor marker, have a good diagnostic value, but its enrichment and detection methods still need to continue to be developed to improve detection accuracy. Therefore, CTCs can be used as an auxiliary means of early detection, which is helpful to the diagnosis and screening of breast cancer.
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Affiliation(s)
- Shiyan Bai
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Shujin Lin
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Ting Lin
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Qiaowen Wang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Cui Cheng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Junru Lin
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Ying Zhang
- Industrial Management Engineering, National University of Singapore, Singapore, Singapore
| | - Xiwen Jiang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Xiao Han
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
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8
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Recent progress in aptamer-based microfluidics for the detection of circulating tumor cells and extracellular vesicles. J Pharm Anal 2023; 13:340-354. [PMID: 37181295 PMCID: PMC10173182 DOI: 10.1016/j.jpha.2023.03.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 02/14/2023] [Accepted: 03/01/2023] [Indexed: 03/09/2023] Open
Abstract
Liquid biopsy is a technology that exhibits potential to detect cancer early, monitor therapies, and predict cancer prognosis due to its unique characteristics, including noninvasive sampling and real-time analysis. Circulating tumor cells (CTCs) and extracellular vesicles (EVs) are two important components of circulating targets, carrying substantial disease-related molecular information and playing a key role in liquid biopsy. Aptamers are single-stranded oligonucleotides with superior affinity and specificity, and they can bind to targets by folding into unique tertiary structures. Aptamer-based microfluidic platforms offer new ways to enhance the purity and capture efficiency of CTCs and EVs by combining the advantages of microfluidic chips as isolation platforms and aptamers as recognition tools. In this review, we first briefly introduce some new strategies for aptamer discovery based on traditional and aptamer-based microfluidic approaches. Then, we subsequently summarize the progress of aptamer-based microfluidics for CTC and EV detection. Finally, we offer an outlook on the future directional challenges of aptamer-based microfluidics for circulating targets in clinical applications.
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Saez J, Garcia-Hernando M, Savva A, Owens RM, Benito-Lopez F, Basabe-Desmonts L. Capture and Release of Cancer Cells Through Smart Bioelectronics. Methods Mol Biol 2023; 2679:305-314. [PMID: 37300625 DOI: 10.1007/978-1-0716-3271-0_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Noninvasive collection of target cells such as circulating tumor cells (CTCs) is crucial for biology and medicine research. Conventional methods of cell collection are often complex, requiring either size-dependent sorting or invasive enzymatic reactions. Here, we show the development of a functional polymer film, which combines the thermoresponsive poly(N-isopropylacrylamide) and the conducting poly(3,4-ethylenedioxythiopene)/poly(styrene sulfonate), and its use for the capture and release of CTCs. When coated onto microfabricated gold electrodes, the proposed polymer films are capable of noninvasively capturing and controllably releasing cells while, at the same time, monitoring these processes with conventional electrical measurements.
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Affiliation(s)
- Janire Saez
- Microfluidics Cluster UPV/EHU, BIOMICs microfluidics Group, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
- Basque Foundation of Science, IKERBASQUE, Bilbao, Spain.
- Bioaraba Health Research Institute, Microfluidics Cluster UPV/EHU, Vitoria-Gasteiz, Spain.
| | - Maite Garcia-Hernando
- Microfluidics Cluster UPV/EHU, BIOMICs microfluidics Group, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Microfluidics Cluster UPV/EHU, Analytical Microsystems & Materials for Lab-on-a-Chip (AMMa-LOAC) Group, Analytical Chemistry Department, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Achilleas Savva
- Department of Chemical Engineering and Biotechnology, Philippa Fawcett Drive, Cambridge, UK
| | - Roisin M Owens
- Department of Chemical Engineering and Biotechnology, Philippa Fawcett Drive, Cambridge, UK
| | - Fernando Benito-Lopez
- Bioaraba Health Research Institute, Microfluidics Cluster UPV/EHU, Vitoria-Gasteiz, Spain
- Microfluidics Cluster UPV/EHU, Analytical Microsystems & Materials for Lab-on-a-Chip (AMMa-LOAC) Group, Analytical Chemistry Department, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Lourdes Basabe-Desmonts
- Microfluidics Cluster UPV/EHU, BIOMICs microfluidics Group, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Basque Foundation of Science, IKERBASQUE, Bilbao, Spain
- Bioaraba Health Research Institute, Microfluidics Cluster UPV/EHU, Vitoria-Gasteiz, Spain
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Kang H, Xiong Y, Ma L, Yang T, Xu X. Recent advances in micro-/nanostructure array integrated microfluidic devices for efficient separation of circulating tumor cells. RSC Adv 2022; 12:34892-34903. [PMID: 36540264 PMCID: PMC9724214 DOI: 10.1039/d2ra06339e] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 11/18/2022] [Indexed: 09/06/2023] Open
Abstract
Circulating tumor cells (CTCs) released from the primary tumor to peripheral blood are promising targets for liquid biopsies. Their biological information is vital for early cancer detection, efficacy assessment, and prognostic monitoring. Despite the tremendous clinical applications of CTCs, development of effective separation techniques are still demanding. Traditional separation methods usually use batch processing for enrichment, which inevitably destroy cell integrity and affect the complete information acquisition. Considering the rarity and heterogeneity of CTCs, it is urgent to develop effective separation methods. Microfluidic chips with precise fluid control at the micron level are promising devices for CTC separation. Their further combination with micro-/nanostructure arrays adds more biomolecule binding sites and exhibit unique fluid barrier effect, which significantly improve the CTC capture efficiency, purity, and sensitivity. This review summarized the recent advances in micro-/nanostructure array integrated microfluidic devices for CTC separation, including microrods, nanowires, and 3D micro-/nanostructures. The mechanisms by which these structures contribute to improved capture efficiency are discussed. Two major categories of separation methods, based on the physical and biological properties of CTCs, are discussed separately. Physical separation includes the design and preparation of micro-/nanostructure arrays, while chemical separation additionally involves the selection and modification of specific capture probes. These emerging technologies are expected to become powerful tools for disease diagnosis in the future.
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Affiliation(s)
- Hanyue Kang
- School of Materials Science and Engineering, Tongji University Shanghai 201804 China
| | - Yuting Xiong
- School of Materials Science and Engineering, Tongji University Shanghai 201804 China
| | - Liang Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University Hangzhou 310058 China
| | - Tongqing Yang
- School of Materials Science and Engineering, Tongji University Shanghai 201804 China
| | - Xiaobin Xu
- School of Materials Science and Engineering, Tongji University Shanghai 201804 China
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11
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A dielectrophoresis-based microfluidic system having double-sided optimized 3D electrodes for label-free cancer cell separation with preserving cell viability. Sci Rep 2022; 12:12100. [PMID: 35840699 PMCID: PMC9287561 DOI: 10.1038/s41598-022-16286-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 07/07/2022] [Indexed: 11/25/2022] Open
Abstract
Early detection of circulating tumor cells (CTCs) in a patient's blood is essential to accurate prognosis and effective cancer treatment monitoring. The methods used to detect and separate CTCs should have a high recovery rate and ensure cells viability for post-processing operations, such as cell culture and genetic analysis. In this paper, a novel dielectrophoresis (DEP)-based microfluidic system is presented for separating MDA-MB-231 cancer cells from various subtypes of WBCs with the practical cell viability approach. Three configurations for the sidewall electrodes are investigated to evaluate the separation performance. The simulation results based on the finite-element method show that semi-circular electrodes have the best performance with a recovery rate of nearly 95% under the same operational and geometric conditions. In this configuration, the maximum applied electric field (1.11 × 105 V/m) to separate MDA-MB-231 is lower than the threshold value for cell electroporation. Also, the Joule heating study in this configuration shows that the cells are not damaged in the fluid temperature gradient (equal to 1 K). We hope that such a complete and step-by-step design is suitable to achieve DEP-based applicable cell separation biochips.
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12
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Çağlayan Arslan Z, Demircan Yalçın Y, Külah H. Label-free enrichment of MCF7 breast cancer cells from leukocytes using continuous flow dielectrophoresis. Electrophoresis 2022; 43:1531-1544. [PMID: 35318696 DOI: 10.1002/elps.202100318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 12/25/2022]
Abstract
Circulating tumor cells (CTCs) present in the bloodstream are strongly linked to the invasive behavior of cancer; therefore, their detection holds great significance for monitoring disease progression. Currently available CTC isolation tools are often based on tumor-specific antigen or cell size approaches. However, these techniques are limited due to the lack of a unique and universal marker for CTCs, and the overlapping size between CTCs and regular blood cells. Dielectrophoresis (DEP), governed by the intrinsic dielectric properties of the particles, is a promising marker-free, accurate, fast, and low-cost technique that enables the isolation of CTCs from blood cells. This study presents a continuous flow, antibody-free DEP-based microfluidic device to concentrate MCF7 breast cancer cells, a well-established CTC model, in the presence of leukocytes extracted from human blood samples. The enrichment strategy was determined according to the DEP responses of the corresponding cells, obtained in our previously reported DEP spectrum study. It was based on the positive-DEP integrated with hydrodynamic focusing under continuous flow. In the proposed device, the parylene microchannel with two inlets and outlets was built on top of rectangular and equally spaced isolated planar electrodes rotated certain degree relative to the main flow (13°). The recovery of MCF7 cells mixed with leukocytes was 74%-98% at a frequency of 1 MHz and a magnitude of 10-12 Vpp . Overall, the results revealed that the presented system successfully concentrates MCF7 cancer cells from leukocytes, ultimately verifying our DEP spectrum study, in which the enrichment frequency and separation strategy of the microfluidic system were determined.
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Affiliation(s)
- Zeynep Çağlayan Arslan
- Department of Electrical and Electronics Engineering, Middle East Technical University (METU), Ankara, Turkey.,METU MEMS Center, Ankara, Turkey
| | - Yağmur Demircan Yalçın
- Department of Electrical and Electronics Engineering, Middle East Technical University (METU), Ankara, Turkey
| | - Haluk Külah
- Department of Electrical and Electronics Engineering, Middle East Technical University (METU), Ankara, Turkey.,METU MEMS Center, Ankara, Turkey
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13
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Wang C, Xu Y, Li S, Zhou Y, Qian Q, Liu Y, Mi X. Designer tetrahedral DNA framework-based microfluidic technology for multivalent capture and release of circulating tumor cells. Mater Today Bio 2022; 16:100346. [PMID: 35833198 PMCID: PMC9272028 DOI: 10.1016/j.mtbio.2022.100346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/26/2022] [Accepted: 06/27/2022] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) have been recognized as a general biomarker for the early detection, diagnosis and therapy monitoring of cancer. Due to their extreme rarity in peripheral blood, the isolation and analysis of CTCs with high efficiency, high purity and high viability remains a tremendous technological challenge. Herein, we combined tetrahedral DNA framework (TDFs), herringbone channel (HB) chip, together with aptamer-triggered hybridization chain reaction (apt-HCR) to develop an efficient microfluidic system (T-μFS) for capture and release of simulated CTCs. The capture efficiency of MCF-7 cells was from 83.3% to 94.2% when the cell numbers ranged from 10 to 103 using our T-μFS in the whole blood. The release efficiency of the MCF-7 cells was 96.2% and the MCF-7 cell viability after release was 94.6% using our T-μFS in PBS buffer. Reculture and RT-qPCR studies showed that there was almost no damage by the capture and release treatment for the MCF-7 cells viability. These results revealed that our T-μFS could be developed as an integrated and automatic technical platform with great performance for multivalent capture and release of CTCs and have a wide application prospect for tumor liquid biopsy.
Three-dimensional amine modified tetrahedral DNA frameworks (TDFs) as rigid scaffolds were anchored on the aldehyde modified substrate of HB-chip, which provided the better spatial orientation compared with single-stranded DNA. Aptamer partially hybridized to an initiator was employed to trigger HCR reaction, and HCR produced modified long products with multi-branched arms for multivalent binding on TDFs to improve the capture efficiency of CTCs. This is the first time that only employed DNA nanostructures in a microfluidic device system to capture CTCs, and all DNA nanostructures could be efficiently removed by enzymes without harming cells.
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14
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Li C, He W, Wang N, Xi Z, Deng R, Liu X, Kang R, Xie L, Liu X. Application of Microfluidics in Detection of Circulating Tumor Cells. Front Bioeng Biotechnol 2022; 10:907232. [PMID: 35646880 PMCID: PMC9133555 DOI: 10.3389/fbioe.2022.907232] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/11/2022] [Indexed: 12/22/2022] Open
Abstract
Tumor metastasis is one of the main causes of cancer incidence and death worldwide. In the process of tumor metastasis, the isolation and analysis of circulating tumor cells (CTCs) plays a crucial role in the early diagnosis and prognosis of cancer patients. Due to the rarity and inherent heterogeneity of CTCs, there is an urgent need for reliable CTCs separation and detection methods in order to obtain valuable information on tumor metastasis and progression from CTCs. Microfluidic technology is increasingly used in various studies of CTCs separation, identification and characterization because of its unique advantages, such as low cost, simple operation, less reagent consumption, miniaturization of the system, rapid detection and accurate control. This paper reviews the research progress of microfluidic technology in CTCs separation and detection in recent years, as well as the potential clinical application of CTCs, looks forward to the application prospect of microfluidic technology in the treatment of tumor metastasis, and briefly discusses the development prospect of microfluidic biosensor.
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Affiliation(s)
- Can Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei He
- Department of Clinical Medical Engineering, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Nan Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhipeng Xi
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Rongrong Deng
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiyu Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ran Kang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Orthopedics, Nanjing Lishui Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Lin Xie
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
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15
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Recent advances for cancer detection and treatment by microfluidic technology, review and update. Biol Proced Online 2022; 24:5. [PMID: 35484481 PMCID: PMC9052508 DOI: 10.1186/s12575-022-00166-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/18/2022] [Indexed: 12/16/2022] Open
Abstract
Numerous cancer-associated deaths are owing to a lack of effective diagnostic and therapeutic approaches. Microfluidic systems for analyzing a low volume of samples offer a precise, quick, and user-friendly technique for cancer diagnosis and treatment. Microfluidic devices can detect many cancer-diagnostic factors from biological fluids and also generate appropriate nanoparticles for drug delivery. Thus, microfluidics may be valuable in the cancer field due to its high sensitivity, high throughput, and low cost. In the present article, we aim to review recent achievements in the application of microfluidic systems for the diagnosis and treatment of various cancers. Although microfluidic platforms are not yet used in the clinic, they are expected to become the main technology for cancer diagnosis and treatment. Microfluidic systems are proving to be more sensitive and accurate for the detection of cancer biomarkers and therapeutic strategies than common assays. Microfluidic lab-on-a-chip platforms have shown remarkable potential in the designing of novel procedures for cancer detection, therapy, and disease follow-up as well as the development of new drug delivery systems for cancer treatment.
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16
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Ming R, Jiang Y, Fan J, An C, Li J, Chen T, Li X. High-Efficiency Capture of Cells by Softening Cell Membrane. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2106547. [PMID: 35112794 DOI: 10.1002/smll.202106547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/30/2021] [Indexed: 06/14/2023]
Abstract
The capture of circulating tumor cells (CTCs) by nanostructured substrate surface is a useful method for early diagnosis of cancer. At present, most methods used to improve the cell capture efficiency are based on changing substrate surface properties. However, there are still some gaps between these methods and practical applications. Here, a method is presented for improving cell capture efficiency from a different perspective, that is, changing the properties of the cells. Concretely, the mechanical properties of the cell membrane are changed by adding Cytochalasin D to soften the cell membrane. Furthermore, a corresponding theoretical model is proposed to explain the experimental results. It is found that cell softening can reduce the resistance of cell adhesion, which makes the adhesion ability stronger. The high-efficiency capture of cells by softening the cell membrane provides a potential method to improve the detection performance of CTCs.
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Affiliation(s)
- Ruiqi Ming
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Ye Jiang
- College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China
| | - Jiaqi Fan
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Chunchun An
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Jinqi Li
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Tongsheng Chen
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- SCNU Qingyuan Institute of Science and Technology Innovation Co. Ltd., Qingyuan, 511517, China
| | - Xinlei Li
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
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17
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A microfluidic device for label-free separation sensitivity enhancement of circulating tumor cells of various and similar size. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2021.118192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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18
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He S, Yu S, Wei J, Ding L, Yang X, Wu Y. New horizons in the identification of circulating tumor cells (CTCs): An emerging paradigm shift in cytosensors. Biosens Bioelectron 2022; 203:114043. [PMID: 35121449 DOI: 10.1016/j.bios.2022.114043] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 01/02/2022] [Accepted: 01/24/2022] [Indexed: 12/11/2022]
Abstract
Circulating tumor cells (CTCs) are cancer cells that are shed from a primary tumor into the bloodstream and function as seeds for cancer metastasis at distant locations. Enrichment and identification methods of CTCs in the blood of patients plays an important role in diagnostic assessments and personalized treatments of cancer. However, the current traditional identification methods not only impact the viability of cells, but also cannot determine the type of cancer cells when the disease is unknown. Hence, new methods to identify CTCs are urgently needed. In this context, many advanced and safe technologies have emerged to distinguish between cancer cells and blood cells, and to distinguish specific types of cancer cells. In this review, at first we have briefly discussed recent advances in technologies related to the enrichment of CTCs, which lay a good foundation for the identification of CTCs. Next, we have summarized state-of-the-art technologies to confirm whether a given cell is indeed a tumor cell and determine the type of tumor cell. Finally, the challenges for application and potential directions of the current identification methods in clinical analysis of CTCs have been discussed.
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Affiliation(s)
- Sitian He
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Songcheng Yu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Jinlan Wei
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Lihua Ding
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiaonan Yang
- Institute of Intelligent Sensing, Zhengzhou University, Zhengzhou, 450001, China.
| | - Yongjun Wu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
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19
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Chícharo A, Caetano DM, Cardoso S, Freitas P. Evolution in Automatized Detection of Cells: Advances in Magnetic Microcytometers for Cancer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1379:413-444. [DOI: 10.1007/978-3-031-04039-9_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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20
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He S, Wei J, Ding L, Yang X, Wu Y. State-of-the-arts techniques and current evolving approaches in the separation and detection of circulating tumor cell. Talanta 2021; 239:123024. [PMID: 34952370 DOI: 10.1016/j.talanta.2021.123024] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 01/01/2023]
Abstract
Circulating tumor cells (CTCs) are cancer cells that shed from the primary tumor and then enter the circulatory system, a small part of which may evolve into metastatic cancer under appropriate microenvironment conditions. The detection of CTCs is a truly noninvasive, dynamic monitor for disease changes, which has considerable clinical implications in the selection of targeted drugs. However, their inherent rarity and heterogeneity pose significant challenges to their isolation and detection. Even the "gold standard", CellSearch™, suffers from high expenses, low capture efficiency, and the consumption of time. With the advancement of CTCs analysis technologies in recent years, the yield and efficiency of CTCs enrichment have gradually been improved, as well as detection sensitivity. In this review, the isolation and detection strategies of CTCs have been completely described and the potential directions for future research and development have also been highlighted through analyzing the challenges faced by current strategies.
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Affiliation(s)
- Sitian He
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
| | - Jinlan Wei
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Lihua Ding
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiaonan Yang
- School of Information Engineering, Zhengzhou University, Zhengzhou, 450001, China.
| | - Yongjun Wu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
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21
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Gao R, Zhan C, Wu C, Lu Y, Cao B, Huang J, Wang F, Yu L. Simultaneous single-cell phenotype analysis of hepatocellular carcinoma CTCs using a SERS-aptamer based microfluidic chip. LAB ON A CHIP 2021; 21:3888-3898. [PMID: 34387639 DOI: 10.1039/d1lc00516b] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Hepatocellular carcinoma (HCC) is a harmful malady that truly debilitates human health, and hence it is of significance to isolate and on-line profile the phenotype of HCC cells for further diagnosis and therapy. We developed a novel strategy for efficient capture and in situ heterogeneous phenotype analysis of circulating tumor cells (CTCs) at the single-cell level based on surface-enhanced Raman scattering (SERS) fingerprint characteristics. Herein, a new microfluidic chip with lantern-like bypass structure was designed to capture CTCs by their large size from whole blood. Furthermore, two types of SERS-aptamer nanotags were fabricated, realizing spectral recognition of single CTCs in accordance with the surface membrane protein expression. Up to 84% of CTCs with a purity of 95% were captured from whole blood samples using the present SERS-aptamer based microfluidic chip at 20 μL min-1. The results showed that the proposed strategy can successfully identify HCC cell subtypes by SERS measurements, which was related to the clinical surface biomarkers. This may open a new avenue for serving as a powerful tool of cancer diagnosis and prognosis evaluation.
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Affiliation(s)
- Rongke Gao
- State Key Laboratory of Advanced Display Technology, School of Instrument Science and Optoelectronic Engineering, Hefei University of Technology, Hefei 230009, China
- College of Control Science and Engineering, China University of Petroleum (East China), Qingdao 266580, China.
| | - Changbiao Zhan
- State Key Laboratory of Advanced Display Technology, School of Instrument Science and Optoelectronic Engineering, Hefei University of Technology, Hefei 230009, China
| | - Chunyu Wu
- State Key Laboratory of Advanced Display Technology, School of Instrument Science and Optoelectronic Engineering, Hefei University of Technology, Hefei 230009, China
| | - Yang Lu
- College of Control Science and Engineering, China University of Petroleum (East China), Qingdao 266580, China.
| | - Baoqiang Cao
- Department of Hepatobiliary Pancreatic Surgery, Anhui No. 2 Provincial People's Hospital, Hefei 230041, China
| | - Jing Huang
- Hefei University of Technology Hospital, Hefei 230009, China
| | - Feng Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Liandong Yu
- College of Control Science and Engineering, China University of Petroleum (East China), Qingdao 266580, China.
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22
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Garcia-Hernando M, Saez J, Savva A, Basabe-Desmonts L, Owens RM, Benito-Lopez F. An electroactive and thermo-responsive material for the capture and release of cells. Biosens Bioelectron 2021; 191:113405. [PMID: 34144472 DOI: 10.1016/j.bios.2021.113405] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 05/13/2021] [Accepted: 06/01/2021] [Indexed: 02/07/2023]
Abstract
Non-invasive collection of target cells is crucial for research in biology and medicine. In this work, we combine a thermo-responsive material, poly(N-isopropylacrylamide), with an electroactive material, poly(3,4-ethylene-dioxythiopene):poly(styrene sulfonate), to generate a smart and conductive copolymer for the label-free and non-invasive detection of the capture and release of cells on gold electrodes by electrochemical impedance spectroscopy. The copolymer is functionalized with fibronectin to capture tumor cells, and undergoes a conformational change in response to temperature, causing the release of cells. Simultaneously, the copolymer acts as a sensor, monitoring the capture and release of cancer cells by electrochemical impedance spectroscopy. This platform has the potential to play a role in top-notch label-free electrical monitoring of human cells in clinical settings.
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Affiliation(s)
- Maite Garcia-Hernando
- Microfluidics Cluster UPV/EHU, Analytical Microsystems & Materials for Lab-on-a-Chip (AMMa-LOAC) Group, Analytical Chemistry Department, University of the Basque Country UPV/EHU, Barrio Sarriena S/n, 48940, Leioa, Spain; Microfluidics Cluster UPV/EHU, BIOMICs Microfluidics Group, Lascaray Research Center, University of the Basque Country UPV/EHU, Avenida Miguel de Unamuno, 3, 01006, Vitoria-Gasteiz, Spain.
| | - Janire Saez
- Department of Chemical Engineering and Biotechnology, Philippa Fawcett Drive, Cambridge, CB3 0AS, UK.
| | - Achilleas Savva
- Department of Chemical Engineering and Biotechnology, Philippa Fawcett Drive, Cambridge, CB3 0AS, UK.
| | - Lourdes Basabe-Desmonts
- Microfluidics Cluster UPV/EHU, BIOMICs Microfluidics Group, Lascaray Research Center, University of the Basque Country UPV/EHU, Avenida Miguel de Unamuno, 3, 01006, Vitoria-Gasteiz, Spain; Bioaraba Health Research Institute, Microfluidics Cluster UPV/EHU, Vitoria-Gasteiz, Spain; BCMaterials, Basque Centre for Materials, Micro and Nanodevices, UPV/EHU Science Park, 48940, Leioa, Spain; Basque Foundation of Science, IKERBASQUE, María Díaz Haroko Kalea, 3, 48013, Bilbao, Spain.
| | - Róisín M Owens
- Department of Chemical Engineering and Biotechnology, Philippa Fawcett Drive, Cambridge, CB3 0AS, UK.
| | - Fernando Benito-Lopez
- Microfluidics Cluster UPV/EHU, Analytical Microsystems & Materials for Lab-on-a-Chip (AMMa-LOAC) Group, Analytical Chemistry Department, University of the Basque Country UPV/EHU, Barrio Sarriena S/n, 48940, Leioa, Spain; Bioaraba Health Research Institute, Microfluidics Cluster UPV/EHU, Vitoria-Gasteiz, Spain; BCMaterials, Basque Centre for Materials, Micro and Nanodevices, UPV/EHU Science Park, 48940, Leioa, Spain.
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23
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Wu L, Wang Y, Xu X, Liu Y, Lin B, Zhang M, Zhang J, Wan S, Yang C, Tan W. Aptamer-Based Detection of Circulating Targets for Precision Medicine. Chem Rev 2021; 121:12035-12105. [PMID: 33667075 DOI: 10.1021/acs.chemrev.0c01140] [Citation(s) in RCA: 317] [Impact Index Per Article: 79.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The past decade has witnessed ongoing progress in precision medicine to improve human health. As an emerging diagnostic technique, liquid biopsy can provide real-time, comprehensive, dynamic physiological and pathological information in a noninvasive manner, opening a new window for precision medicine. Liquid biopsy depends on the sensitive and reliable detection of circulating targets (e.g., cells, extracellular vesicles, proteins, microRNAs) from body fluids, the performance of which is largely governed by recognition ligands. Aptamers are single-stranded functional oligonucleotides, capable of folding into unique tertiary structures to bind to their targets with superior specificity and affinity. Their mature evolution procedure, facile modification, and affinity regulation, as well as versatile structural design and engineering, make aptamers ideal recognition ligands for liquid biopsy. In this review, we present a broad overview of aptamer-based liquid biopsy techniques for precision medicine. We begin with recent advances in aptamer selection, followed by a summary of state-of-the-art strategies for multivalent aptamer assembly and aptamer interface modification. We will further describe aptamer-based micro-/nanoisolation platforms, aptamer-enabled release methods, and aptamer-assisted signal amplification and detection strategies. Finally, we present our perspectives regarding the opportunities and challenges of aptamer-based liquid biopsy for precision medicine.
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Affiliation(s)
- Lingling Wu
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yidi Wang
- Collaborative Innovation Center of Chemistry for Energy Materials, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Xing Xu
- Collaborative Innovation Center of Chemistry for Energy Materials, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Yilong Liu
- Collaborative Innovation Center of Chemistry for Energy Materials, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Bingqian Lin
- Collaborative Innovation Center of Chemistry for Energy Materials, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Mingxia Zhang
- Collaborative Innovation Center of Chemistry for Energy Materials, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Jialu Zhang
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Shuang Wan
- Collaborative Innovation Center of Chemistry for Energy Materials, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Chaoyong Yang
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Collaborative Innovation Center of Chemistry for Energy Materials, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Weihong Tan
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, China.,The Cancer Hospital of the University of Chinese Academy of Sciences, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
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24
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Xu L, Li R, Wang Z, Cui H, Li W, Yu M, Guo SS, Zhao XZ. Electrospun degradable Zn-Mn oxide hierarchical nanofibers for specific capture and efficient release of circulating tumor cells. NANOTECHNOLOGY 2020; 31:495102. [PMID: 32990263 DOI: 10.1088/1361-6528/abb48b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Constructing biological affinity devices is considered as an effective strategy for isolating circulating tumor cells (CTCs), and electrospun nanofibers (ESNFs) have recently received attention. However, the current research focuses on polymer fibers, and fabricating stimuli-responsive inorganic nanofibers for cancer diagnosis and analysis is still challenging. In this work, Zn-Mn oxide nanofibers (ZnMnNFs) are used to capture and purify cancer cells after modification with specific antibodies. Then, the hierarchical nanofibers are degraded by reductive weak acid to release the captured cells efficiently without residues. Fusion of Zn and Mn, two transition metals, enhances the surface activity of oxides so that ZnMnNFs are easier to be degraded and modified. By using MCF-7 cancer cells, the cell capture efficiency of ZnMnNFs is up to 88.2%. Furthermore, by using citric acid, it is discovered that, by comparison with Mn oxide nanofibers, the cell release efficiency of ZnMnNFs is improved to 95.1% from 15.4%. In addition, the viability of released cells exceeds 90%. Lastly, the robustness of ZnMnNFs substrates is tested in peripheral blood from breast cancer patients (BCP) and colorectal cancer patients (CCP). Combined with fluorescence labeling, CTCs are confirmed to be isolated from all the clinical samples. This is the first trial of using ternary inorganic ESNFs for cancer cell capture. It is anticipated that the degradable ESNFs will provide biocompatible theranostic platforms and overcome the current limitations of cell release for high-precision gene analysis.
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Affiliation(s)
- Longguang Xu
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Rui Li
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Zixiang Wang
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Heng Cui
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Wei Li
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Mingxia Yu
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, People's Republic of China
| | - Shi-Shang Guo
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Xing-Zhong Zhao
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
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Herath S, Razavi Bazaz S, Monkman J, Ebrahimi Warkiani M, Richard D, O’Byrne K, Kulasinghe A. Circulating tumor cell clusters: Insights into tumour dissemination and metastasis. Expert Rev Mol Diagn 2020; 20:1139-1147. [DOI: 10.1080/14737159.2020.1846523] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Sayuri Herath
- Department of Medical Laboratory Sciences, Faculty of Health Sciences, The Open University of Sri Lanka, Colombo, Sri Lanka
| | - Sajad Razavi Bazaz
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
| | - James Monkman
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
- Translational Research Institute, Woolloongabba, QLD, Australia
- Cancer and Ageing Research Program, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
- Institute of Molecular Medicine, Sechenov First Moscow State University, Moscow, Russia
| | - Derek Richard
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
- Translational Research Institute, Woolloongabba, QLD, Australia
- Cancer and Ageing Research Program, Australia
| | - Ken O’Byrne
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
- Translational Research Institute, Woolloongabba, QLD, Australia
- Cancer and Ageing Research Program, Australia
- Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Arutha Kulasinghe
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
- Translational Research Institute, Woolloongabba, QLD, Australia
- Cancer and Ageing Research Program, Australia
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Kim IA, Hur JY, Kim HJ, Lee SE, Kim WS, Lee KY. Liquid biopsy using extracellular vesicle-derived DNA in lung adenocarcinoma. J Pathol Transl Med 2020; 54:453-461. [PMID: 33027851 PMCID: PMC7674759 DOI: 10.4132/jptm.2020.08.13] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022] Open
Abstract
Blood liquid biopsy has emerged as a way of overcoming the clinical limitations of repeat biopsy by testing for the presence of acquired resistance mutations to therapeutic agents. Despite its merits of repeatability and non-invasiveness, this method is currently only used as a supplemental test due to a relatively low sensitivity rate of 50%–60%, and cannot replace tissue biopsy. The circulating tumor DNAs used in blood liquid biopsies are passive products of fragmented DNA with a short half-life released following tumor cell death; the low sensitivity seen with liquid blood biopsy results from this instability, which makes increasing the sensitivity of this test fundamentally difficult. Extracellular vesicles (EVs) are ideal carriers of cancer biomarkers, as cancer cells secret an abundance of EVs, and the contents of tumor cell-originated EVs reflect the molecular and genetic composition of parental cells. In addition, EV-derived DNAs (EV DNAs) consist of large-sized genomic DNAs and tumor-specific oncogenic mutant DNAs. For these reasons, liquid biopsy using EV DNA has the potential to overcome issues arising from tissue shortages associated with small biopsies, which are often seen in lung cancer patients, and the biopsy product can be used in other diagnostic methods, such as epidermal growth factor receptor (EGFR) mutation testing and next-generation sequencing (NGS). A higher sensitivity can be achieved when EV DNAs obtained from bronchoalveolar lavage fluid (BALF) are used rather than those from blood. BALF, when obtained close to the tumor site, is a promising liquid biopsy tool, as it enables the gathering of both cellular and non-cellular fractions of the tumor microenvironment, and provides increased diagnostic sensitivity when compared to blood.
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Affiliation(s)
- In Ae Kim
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Korea.,Department of Pulmonary Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jae Young Hur
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Korea.,Department of Pathology, Konkuk University School of Medicine, Seoul, Korea
| | - Hee Joung Kim
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Korea.,Department of Pulmonary Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Seung Eun Lee
- Department of Pathology, Konkuk University School of Medicine, Seoul, Korea
| | - Wan Seop Kim
- Department of Pathology, Konkuk University School of Medicine, Seoul, Korea
| | - Kye Young Lee
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Korea.,Department of Pulmonary Medicine, Konkuk University School of Medicine, Seoul, Korea
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Park JE, Oh N, Nam H, Park JH, Kim S, Jeon JS, Yang M. Efficient Capture and Raman Analysis of Circulating Tumor Cells by Nano-Undulated AgNPs-rGO Composite SERS Substrates. SENSORS (BASEL, SWITZERLAND) 2020; 20:E5089. [PMID: 32906807 PMCID: PMC7570931 DOI: 10.3390/s20185089] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 09/02/2020] [Accepted: 09/05/2020] [Indexed: 12/12/2022]
Abstract
The analysis of circulating tumor cells (CTCs) in the peripheral blood of cancer patients is critical in clinical research for further investigation of tumor progression and metastasis. In this study, we present a novel surface-enhanced Raman scattering (SERS) substrate for the efficient capture and characterization of cancer cells using silver nanoparticles-reduced graphene oxide (AgNPs-rGO) composites. A pulsed laser reduction of silver nanowire-graphene oxide (AgNW-GO) mixture films induces hot-spot formations among AgNPs and artificial biointerfaces consisting of rGOs. We also use in situ electric field-assisted fabrication methods to enhance the roughness of the SERS substrate. The AgNW-GO mixture films, well suited for the proposed process due to its inherent electrophoretic motion, is adjusted between indium tin oxide (ITO) transparent electrodes and the nano-undulated surface is generated by applying direct-current (DC) electric fields during the laser process. As a result, MCF7 breast cancer cells are efficiently captured on the AgNPs-rGO substrates, about four times higher than the AgNWs-GO films, and the captured living cells are successfully analyzed by SERS spectroscopy. Our newly designed bifunctional substrate can be applied as an effective system for the capture and characterization of CTCs.
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Affiliation(s)
- Jong-Eun Park
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (J.-E.P.); (H.N.); (S.K.)
| | - Nuri Oh
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (N.O.); (J.-H.P.)
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Hyeono Nam
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (J.-E.P.); (H.N.); (S.K.)
| | - Ji-Ho Park
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (N.O.); (J.-H.P.)
| | - Sanha Kim
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (J.-E.P.); (H.N.); (S.K.)
| | - Jessie S. Jeon
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (J.-E.P.); (H.N.); (S.K.)
| | - Minyang Yang
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (J.-E.P.); (H.N.); (S.K.)
- Department of Mechanical Engineering, State University of New York Korea, Incheon 21985, Korea
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28
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Rotoli D, Santana-Viera L, Ibba ML, Esposito CL, Catuogno S. Advances in Oligonucleotide Aptamers for NSCLC Targeting. Int J Mol Sci 2020; 21:ijms21176075. [PMID: 32842557 PMCID: PMC7504093 DOI: 10.3390/ijms21176075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 02/07/2023] Open
Abstract
Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, with the highest incidence in developed countries. NSCLC patients often face resistance to currently available therapies, accounting for frequent relapses and poor prognosis. Indeed, despite great recent advancements in the field of NSCLC diagnosis and multimodal therapy, most patients are diagnosed at advanced metastatic stage, with a very low overall survival. Thus, the identification of new effective diagnostic and therapeutic options for NSCLC patients is a crucial challenge in oncology. A promising class of targeting molecules is represented by nucleic-acid aptamers, short single-stranded oligonucleotides that upon folding in particular three dimensional (3D) structures, serve as high affinity ligands towards disease-associated proteins. They are produced in vitro by SELEX (systematic evolution of ligands by exponential enrichment), a combinatorial chemistry procedure, representing an important tool for novel targetable biomarker discovery of both diagnostic and therapeutic interest. Aptamer-based approaches are promising options for NSCLC early diagnosis and targeted therapy and may overcome the key obstacles of currently used therapeutic modalities, such as the high toxicity and patients’ resistance. In this review, we highlight the most important applications of SELEX technology and aptamers for NSCLC handling.
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Affiliation(s)
- Deborah Rotoli
- Institute Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), 80145 Naples, Italy; (D.R.); (L.S.-V.)
| | - Laura Santana-Viera
- Institute Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), 80145 Naples, Italy; (D.R.); (L.S.-V.)
| | - Maria L. Ibba
- Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of Naples, 80131 Naples, Italy;
| | - Carla L. Esposito
- Institute Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), 80145 Naples, Italy; (D.R.); (L.S.-V.)
- Correspondence: (C.L.E.); (S.C.); Tel.: +39-081-3722343 (C.L.E. & S.C.)
| | - Silvia Catuogno
- Institute Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), 80145 Naples, Italy; (D.R.); (L.S.-V.)
- Correspondence: (C.L.E.); (S.C.); Tel.: +39-081-3722343 (C.L.E. & S.C.)
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Nasiri R, Shamloo A, Ahadian S, Amirifar L, Akbari J, Goudie MJ, Lee K, Ashammakhi N, Dokmeci MR, Di Carlo D, Khademhosseini A. Microfluidic-Based Approaches in Targeted Cell/Particle Separation Based on Physical Properties: Fundamentals and Applications. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e2000171. [PMID: 32529791 DOI: 10.1002/smll.202000171] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/15/2020] [Indexed: 06/11/2023]
Abstract
Cell separation is a key step in many biomedical research areas including biotechnology, cancer research, regenerative medicine, and drug discovery. While conventional cell sorting approaches have led to high-efficiency sorting by exploiting the cell's specific properties, microfluidics has shown great promise in cell separation by exploiting different physical principles and using different properties of the cells. In particular, label-free cell separation techniques are highly recommended to minimize cell damage and avoid costly and labor-intensive steps of labeling molecular signatures of cells. In general, microfluidic-based cell sorting approaches can separate cells using "intrinsic" (e.g., fluid dynamic forces) versus "extrinsic" external forces (e.g., magnetic, electric field, etc.) and by using different properties of cells including size, density, deformability, shape, as well as electrical, magnetic, and compressibility/acoustic properties to select target cells from a heterogeneous cell population. In this work, principles and applications of the most commonly used label-free microfluidic-based cell separation methods are described. In particular, applications of microfluidic methods for the separation of circulating tumor cells, blood cells, immune cells, stem cells, and other biological cells are summarized. Computational approaches complementing such microfluidic methods are also explained. Finally, challenges and perspectives to further develop microfluidic-based cell separation methods are discussed.
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Affiliation(s)
- Rohollah Nasiri
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Amir Shamloo
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Samad Ahadian
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
| | - Leyla Amirifar
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Javad Akbari
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Marcus J Goudie
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - KangJu Lee
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Nureddin Ashammakhi
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Mehmet R Dokmeci
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
- Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Dino Di Carlo
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Ali Khademhosseini
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
- Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
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30
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Khizar S, Ben Halima H, Ahmad NM, Zine N, Errachid A, Elaissari A. Magnetic nanoparticles in microfluidic and sensing: From transport to detection. Electrophoresis 2020; 41:1206-1224. [DOI: 10.1002/elps.201900377] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 04/15/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Sumera Khizar
- Université de Lyon LAGEP, UMR‐5007, CNRS, Université Lyon 1, 5007 43 Bd 11 Novembre 1918 Villeurbanne F‐69622 France
- Polymer Research Lab School of Chemical and Materials Engineering (SCME) National University of Sciences and Technology (NUST) H‐12 Sector Islamabad 44000 Pakistan
| | - Hamdi Ben Halima
- Université de Lyon Institut des Science Analytiques UMR 5280, CNRS Université Lyon 1 ENS Lyon-5, rue de la Doua Villeurbanne F‐69100 France
| | - Nasir M. Ahmad
- Polymer Research Lab School of Chemical and Materials Engineering (SCME) National University of Sciences and Technology (NUST) H‐12 Sector Islamabad 44000 Pakistan
| | - Nadia Zine
- Université de Lyon Institut des Science Analytiques UMR 5280, CNRS Université Lyon 1 ENS Lyon-5, rue de la Doua Villeurbanne F‐69100 France
| | - Abdelhamid Errachid
- Université de Lyon Institut des Science Analytiques UMR 5280, CNRS Université Lyon 1 ENS Lyon-5, rue de la Doua Villeurbanne F‐69100 France
| | - Abdelhamid Elaissari
- Université de Lyon LAGEP, UMR‐5007, CNRS, Université Lyon 1, 5007 43 Bd 11 Novembre 1918 Villeurbanne F‐69622 France
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Wang S, Hong S, Cai S, Lei J, Chen J, Zhang N, Ai Z, Liu K, Tang M. Negative depletion mediated brightfield circulating tumour cell identification strategy on microparticle-based microfluidic chip. J Nanobiotechnology 2020; 18:70. [PMID: 32381091 PMCID: PMC7206695 DOI: 10.1186/s12951-020-00623-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/27/2020] [Indexed: 02/08/2023] Open
Abstract
Background The most convenient circulating tumor cells (CTCs) identification method is direct analysis of cells under bright field microscopy by which CTCs can be comprehensive studied based on morphology, phenotype or even cellular function. However, universal cell markers and a standard tumour cell map do not exist, thus limiting the clinical application of CTCs. Results This paper focuses on an automatic and convenient negative depletion strategy for circulating tumour cell identification under bright field microscopy. In this strategy, immune microparticles (IMPs) are applied to negatively label white blood cells rather than the tumour cells, such that tumour cells can be directly distinguished under brightfield of the microscopy. In this way, all of the heterogeneous tumour cells and their phenotype properties can be retained for further cancer-related studies. In addition, a wedge-shaped microfluidic chip is constructed for heterogeneous CTC pre-purification and enrichment by size, thus significantly decreasing the interference of haematological cells. Additionally, all cell treatments are processed automatically, and the tumour cells can be rapidly counted and distinguished via customized cell analytical software, showing high detection efficiency and automation. This IMPs based negative cell labelling strategy can also be combined with other classic cell identification methods, thus demonstrating its excellent compatibility. Conclusion This identification strategy features simple and harmless for tumour cells, as well as excellent accuracy and efficiency. And the low equipment demand and high automation level make it promise for extensive application in basic medical institutions.
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Affiliation(s)
- Shuibing Wang
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Shaoli Hong
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Shijia Cai
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Jia Lei
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Jinyao Chen
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Nangang Zhang
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Zhao Ai
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Kan Liu
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China.
| | - Man Tang
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China.
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Wu S, Wang Y, Shi D. Positively Charged Magnetic Nanoparticles for Capture of Circulating Tumor Cells from Clinical Blood Samples. ACTA ACUST UNITED AC 2020. [DOI: 10.1142/s1793984419710016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Isolation of circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and metastasis diagnosis. Although many new detection methods have emerged in recent years, the detection of CTCs is a current challenge due to lack of specific and sensitive markers. In our previous work, cancer cell surfaces, from over 20 cancer cell lines, have been shown to be negatively-charged regardless of their phenotype by using electrically-charged nanoparticles as a probe. The strong electrostatic interaction between the negative cancer cells and positively charged nanoparticles can well remain in a physiological liquid environment in the presence of serum proteins, enabling effective binding between them. As a result, the cancer cells can be magnetically separated by employing an external magnet. In this technical report, we present preliminary results on the investigation of CTC isolation from both mimetic and clinical blood samples. We show high CTC detection sensitivity by the positively-charged magnetic nanoparticles (PMNs) even at the original concentration of 10 cells per mL mimetic blood sample. The CTCs in the peripheral blood of colorectal cancer patients were isolated and identified by cellular morphology and immunofluorescence staining.
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Affiliation(s)
- Shengming Wu
- The Institute for Translational Nanomedicine, Shanghai East Hospital, The Institute for Biomedical Engineering and Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China
| | - Yilong Wang
- The Institute for Translational Nanomedicine, Shanghai East Hospital, The Institute for Biomedical Engineering and Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China
| | - Donglu Shi
- The Materials Science and Engineering Program, Department of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH 45221, USA
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Lee AC, Svedlund J, Darai E, Lee Y, Lee D, Lee HB, Kim SM, Kim O, Bae HJ, Choi A, Lee S, Jeong Y, Song SW, Choi Y, Yeom H, Lee CS, Han W, Lee DS, Jang JY, Madaboosi N, Nilsson M, Kwon S. OPENchip: an on-chip in situ molecular profiling platform for gene expression analysis and oncogenic mutation detection in single circulating tumour cells. LAB ON A CHIP 2020; 20:912-922. [PMID: 32057051 DOI: 10.1039/c9lc01248f] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Liquid biopsy holds promise towards practical implementation of personalized theranostics of cancer. In particular, circulating tumour cells (CTCs) can provide clinically actionable information that can be directly linked to prognosis or therapy decisions. In this study, gene expression patterns and genetic mutations in single CTCs are simultaneously analysed by strategically combining microfluidic technology and in situ molecular profiling technique. Towards this, the development and demonstration of the OPENchip (On-chip Post-processing ENabling chip) platform for single CTC analysis by epithelial CTC enrichment and subsequent in situ molecular profiling is reported. For in situ molecular profiling, padlock probes that identify specific desired targets to examine biomarkers of clinical relevance in cancer diagnostics were designed and used to create libraries of rolling circle amplification products. We characterize the OPENchip in terms of its capture efficiency and capture purity, and validate the probe design using different cell lines. By integrating the obtained results, molecular analyses of CTCs from metastatic breast cancer (HER2 (ERBB2) gene expression and PIK3CA mutations) and metastatic pancreatic cancer (KRAS gene mutations) patients were demonstrated without any off-chip processes. The results substantiate the potential implementation of early molecular detection of cancer through sequencing-free liquid biopsy.
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Affiliation(s)
- Amos C Lee
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, 08826, South Korea.
| | - Jessica Svedlund
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Evangelia Darai
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Yongju Lee
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, 08826, South Korea
| | - Daewon Lee
- BK21+ Creative Research Engineer Development for IT, Seoul National University, Seoul, 08826, South Korea
| | - Han-Byoel Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea and Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Sung-Min Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Okju Kim
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, 08826, South Korea
| | - Hyung Jong Bae
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Ahyoun Choi
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, 08826, South Korea.
| | - Sumin Lee
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, 08826, South Korea
| | - Yunjin Jeong
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, 08826, South Korea
| | - Seo Woo Song
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, 08826, South Korea
| | - Yeongjae Choi
- Nano Systems Institute, Seoul National University, Seoul, Republic of Korea
| | - Huiran Yeom
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, 08826, South Korea
| | - Caleb S Lee
- Departments of Bioengineering and Materials Science and Engineering, University of California, Berkeley, CA 94720, USA
| | - Wonshik Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea and Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea and Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Dong Soon Lee
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea and Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea and Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Narayanan Madaboosi
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Mats Nilsson
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Sunghoon Kwon
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, 08826, South Korea. and Department of Electrical and Computer Engineering, Seoul National University, Seoul, 08826, South Korea and BK21+ Creative Research Engineer Development for IT, Seoul National University, Seoul, 08826, South Korea and Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea and Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, 08826, Republic of Korea
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Lin Z, Luo G, Du W, Kong T, Liu C, Liu Z. Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor-On-A-Chip. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e1903899. [PMID: 31747120 DOI: 10.1002/smll.201903899] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/13/2019] [Indexed: 05/03/2023]
Abstract
Cancer remains the leading cause of death worldwide despite the enormous efforts that are made in the development of cancer biology and anticancer therapeutic treatment. Furthermore, recent studies in oncology have focused on the complex cancer metastatic process as metastatic disease contributes to more than 90% of tumor-related death. In the metastatic process, isolation and analysis of circulating tumor cells (CTCs) play a vital role in diagnosis and prognosis of cancer patients at an early stage. To obtain relevant information on cancer metastasis and progression from CTCs, reliable approaches are required for CTC detection and isolation. Additionally, experimental platforms mimicking the tumor microenvironment in vitro give a better understanding of the metastatic microenvironment and antimetastatic drugs' screening. With the advancement of microfabrication and rapid prototyping, microfluidic techniques are now increasingly being exploited to study cancer metastasis as they allow precise control of fluids in small volume and rapid sample processing at relatively low cost and with high sensitivity. Recent advancements in microfluidic platforms utilized in various methods for CTCs' isolation and tumor models recapitulating the metastatic microenvironment (tumor-on-a-chip) are comprehensively reviewed. Future perspectives on microfluidics for cancer metastasis are proposed.
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Affiliation(s)
- Zhengjie Lin
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, China
| | - Guanyi Luo
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Weixiang Du
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Tiantian Kong
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Changkun Liu
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, China
| | - Zhou Liu
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, China
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Siemer S, Wünsch D, Khamis A, Lu Q, Scherberich A, Filippi M, Krafft MP, Hagemann J, Weiss C, Ding GB, Stauber RH, Gribko A. Nano Meets Micro-Translational Nanotechnology in Medicine: Nano-Based Applications for Early Tumor Detection and Therapy. NANOMATERIALS 2020; 10:nano10020383. [PMID: 32098406 PMCID: PMC7075286 DOI: 10.3390/nano10020383] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/03/2020] [Accepted: 02/15/2020] [Indexed: 02/07/2023]
Abstract
Nanomaterials have great potential for the prevention and treatment of cancer. Circulating tumor cells (CTCs) are cancer cells of solid tumor origin entering the peripheral blood after detachment from a primary tumor. The occurrence and circulation of CTCs are accepted as a prerequisite for the formation of metastases, which is the major cause of cancer-associated deaths. Due to their clinical significance CTCs are intensively discussed to be used as liquid biopsy for early diagnosis and prognosis of cancer. However, there are substantial challenges for the clinical use of CTCs based on their extreme rarity and heterogeneous biology. Therefore, methods for effective isolation and detection of CTCs are urgently needed. With the rapid development of nanotechnology and its wide applications in the biomedical field, researchers have designed various nano-sized systems with the capability of CTCs detection, isolation, and CTCs-targeted cancer therapy. In the present review, we summarize the underlying mechanisms of CTC-associated tumor metastasis, and give detailed information about the unique properties of CTCs that can be harnessed for their effective analytical detection and enrichment. Furthermore, we want to give an overview of representative nano-systems for CTC isolation, and highlight recent achievements in microfluidics and lab-on-a-chip technologies. We also emphasize the recent advances in nano-based CTCs-targeted cancer therapy. We conclude by critically discussing recent CTC-based nano-systems with high therapeutic and diagnostic potential as well as their biocompatibility as a practical example of applied nanotechnology.
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Affiliation(s)
- Svenja Siemer
- Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Désirée Wünsch
- Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Aya Khamis
- Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Qiang Lu
- Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Arnaud Scherberich
- Laboratory of Tissue Engineering, Universitätspital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland (M.F.)
| | - Miriam Filippi
- Laboratory of Tissue Engineering, Universitätspital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland (M.F.)
| | - Marie Pierre Krafft
- Institut Charles Sadron (CNRS), University of Strasbourg, 23 rue du Loess, 67034 Strasbourg Cedex, France
| | - Jan Hagemann
- Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Carsten Weiss
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Postfach 3640, 76021 Karlsruhe, Germany
| | - Guo-Bin Ding
- Institute for Biotechnology, Shanxi University, No. 92 Wucheng Road, 030006 Taiyuan, China
| | - Roland H. Stauber
- Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany
- Institute for Biotechnology, Shanxi University, No. 92 Wucheng Road, 030006 Taiyuan, China
- Correspondence: (R.H.S.); (A.G.); Tel.: +49-6131-176030 (A.G.)
| | - Alena Gribko
- Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany
- Correspondence: (R.H.S.); (A.G.); Tel.: +49-6131-176030 (A.G.)
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Çağlayan Z, Demircan Yalçın Y, Külah H. Examination of the dielectrophoretic spectra of MCF7 breast cancer cells and leukocytes. Electrophoresis 2020; 41:345-352. [PMID: 31925804 DOI: 10.1002/elps.201900374] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 12/31/2019] [Accepted: 01/06/2020] [Indexed: 11/08/2022]
Abstract
The detection of circulating tumor cells (CTCs) in blood is crucial to assess metastatic progression and to guide therapy. Dielectrophoresis (DEP) is a powerful cell surface marker-free method that allows intrinsic dielectric properties of suspended cells to be exploited for CTC enrichment/isolation from blood. Design of a successful DEP-based CTC enrichment/isolation system requires that the DEP response of the targeted particles should accurately be known. This paper presents a DEP spectrum method to investigate the DEP spectra of cells without directly analyzing their membrane and cytoplasmic properties in contrast to the methods in literature, which employ theoretical assumptions and complex modeling. Integrating electric field simulations based on DEP theory with the experimental data enables determination of the DEP spectra of leukocyte subpopulations, polymorphonuclear and mononuclear leukocytes, and MCF7 breast cancer cells as a model of CTC due to their metastatic origin over the frequency range 100 kHz-50 MHz at 10 Vpp . In agreement with earlier findings, differential DEP responses were detected for mononuclear and polymorphonuclear leukocytes due to the richness of the cell surface features and morphologies of the different leukocyte types. The data reveal that the strength of the DEP force exerted on MCF7 cells was particularly high between 850 kHz and 20 MHz. These results illustrate that the proposed technique has the potential to provide a generic platform to identify DEP responses of different biological particles.
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Affiliation(s)
- Zeynep Çağlayan
- Department of Electrical and Electronics Engineering, Middle East Technical University, Ankara, Turkey.,METU MEMS Research and Application Center, Ankara, Turkey
| | - Yağmur Demircan Yalçın
- Department of Electrical and Electronics Engineering, Middle East Technical University, Ankara, Turkey.,Mikro Biyosistemler Electronics Inc., Ankara, Turkey
| | - Haluk Külah
- Department of Electrical and Electronics Engineering, Middle East Technical University, Ankara, Turkey.,METU MEMS Research and Application Center, Ankara, Turkey.,Mikro Biyosistemler Electronics Inc., Ankara, Turkey
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Salvianti F, Costanza F, Sonnati G, Pinzani P. Detection and Characterization of Circulating Tumor Cells by Quantitative Real-Time PCR. Methods Mol Biol 2020; 2065:139-151. [PMID: 31578693 DOI: 10.1007/978-1-4939-9833-3_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
We propose two different approaches involving the use of quantitative real-time PCR for the detection or analysis of circulating tumor cells. In one case cells are indirectly identified through the expression of a marker mRNA, while in the other one cells are enriched by size prior to be submitted to mutational analysis for a specific target. Both methods have been successfully applied to the study of circulating melanoma cells.
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Affiliation(s)
- Francesca Salvianti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Filomena Costanza
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Gemma Sonnati
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Pamela Pinzani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
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Abstract
Circulating tumor cells (CTCs) are responsible for the metastatic spread of cancer and therefore are extremely valuable not only for basic research on cancer metastasis but also as potential biomarkers in diagnosing and managing cancer in the clinic. While relatively non-invasive access to the blood tissue presents an opportunity, CTCs are mixed with approximately billion-times more-populated blood cells in circulation. Therefore, the accuracy of technologies for reliable enrichment of the rare CTC population from blood samples is critical to the success of downstream analyses. The focus of this chapter is to provide the reader an overview of significant advances made in the development of diverse CTC enrichment technologies by presenting the strengths of individual techniques in addition to specific challenges remaining to be addressed.
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Li W, Wang H, Zhao Z, Gao H, Liu C, Zhu L, Wang C, Yang Y. Emerging Nanotechnologies for Liquid Biopsy: The Detection of Circulating Tumor Cells and Extracellular Vesicles. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1805344. [PMID: 30589111 DOI: 10.1002/adma.201805344] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 10/29/2018] [Indexed: 05/18/2023]
Abstract
Liquid biopsy enables noninvasive and dynamic analysis of molecular or cellular biomarkers, and therefore holds great potential for the diagnosis, prognosis, monitoring of disease progress and treatment efficacy, understanding of disease mechanisms, and identification of therapeutic targets for drug development. In this review, the recent progress in nanomaterials, nanostructures, nanodevices, and nanosensors for liquid biopsy is summarized, with a focus on the detection and molecular characterization of circulating tumor cells (CTCs) and extracellular vesicles (EVs). The developments and advances of nanomaterials and nanostructures in enhancing the sensitivity, specificity, and purity for the detection of CTCs and EVs are discussed. Sensing techniques for signal transduction and amplification as well as visualization strategies are also discussed. New technologies for the reversible release of the isolated CTCs and EVs and for single-CTC/EV analysis are summarized. Emerging microfluidic platforms for the integral on-chip isolation, detection, and molecular analysis are also included. The opportunities, challenges, and prospects of these innovative materials and technologies, especially with regard to their feasibility in clinical applications, are discussed. The applications of nanotechnology-based liquid biopsy will bring new insight into the clinical practice in monitoring and treatment of tumor and other significant diseases.
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Affiliation(s)
- Wenzhe Li
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Huayi Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Zijian Zhao
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Houqian Gao
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Changliang Liu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Ling Zhu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Chen Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yanlian Yang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
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Li Q, Cui S, Xu Y, Wang Y, Jin F, Si H, Li L, Tang B. Consecutive Sorting and Phenotypic Counting of CTCs by an Optofluidic Flow Cytometer. Anal Chem 2019; 91:14133-14140. [DOI: 10.1021/acs.analchem.9b04035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Qingling Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China
| | - Shuang Cui
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China
| | - Yuehan Xu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China
| | - Yiguo Wang
- Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, 250014, P.R. China
| | - Feng Jin
- Department of Thoracic Surgery, Shandong Provincial Chest Hospital Affiliated with Shandong University, Jinan, 250013, P.R. China
| | - Haibin Si
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China
| | - Lu Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China
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Yue WQ, Tan Z, Li XP, Liu FF, Wang C. Micro/nanofluidic technologies for efficient isolation and detection of circulating tumor cells. Trends Analyt Chem 2019. [DOI: 10.1016/j.trac.2019.06.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Wu L, Zhu L, Huang M, Song J, Zhang H, Song Y, Wang W, Yang C. Aptamer-based microfluidics for isolation, release and analysis of circulating tumor cells. Trends Analyt Chem 2019. [DOI: 10.1016/j.trac.2019.05.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Jia M, Mao Y, Wu C, Wang S, Zhang H. A platform for primary tumor origin identification of circulating tumor cells via antibody cocktail-based in vivo capture and specific aptamer-based multicolor fluorescence imaging strategy. Anal Chim Acta 2019; 1082:136-145. [PMID: 31472702 DOI: 10.1016/j.aca.2019.07.051] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 06/23/2019] [Accepted: 07/22/2019] [Indexed: 02/05/2023]
Abstract
Circulating tumor cells (CTCs) are expected to serve as a blood-based biomarker in the diagnosis of cancers at an early stage, providing an opportunity to increase the survival of cancer patients. Current techniques for CTC detection were designed for some particular types of cancer with confirmed primary tumor origin. In this work, a platform for the detection of two cancer types and the identification of the primary tumor origin of CTCs was established to meet the requirement of cancer diagnosis and clinical application. A combined strategy based on in vivo capture method using antibody cocktail and multicolor fluorescence imaging using aptamer was designed to achieve the high-efficiency capture of CTCs and the accurate location of the primary tumor. An antibody cocktail of epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR) was applied to capture breast cancer CTCs and hepatocellular CTCs in vivo. The capture efficiency of hepatocellular CTCs was significantly increased from 3.17% to 26.67% and the capture efficiency of breast cancer CTCs slightly increased from 27.00% to 29.84% compared with EpCAM-based capture of CTCs. Meanwhile, the primary tumor origins of breast cancer CTCs and hepatocellular CTCs were simultaneously distinguished by specific aptamer-based fluorescence probes without any signal crosstalk. The results of in vivo experiments using the dual tumor-bearing mouse model confirmed the feasibility of this method to capture CTCs and identify primary tumor origins. This simple and efficient approach has potential for future applications in cancer diagnosis and prognosis.
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Affiliation(s)
- Min Jia
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan, 250014, PR China
| | - Yifei Mao
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan, 250014, PR China
| | - Chuanchen Wu
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan, 250014, PR China
| | - Shuo Wang
- School of Medicine, Nankai University, Tianjin, 300457, China.
| | - Hongyan Zhang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan, 250014, PR China.
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44
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Ultrasensitive label-free detection of circulating tumor cells using conductivity matching of two-dimensional semiconductor with cancer cell. Biosens Bioelectron 2019; 142:111520. [PMID: 31330418 DOI: 10.1016/j.bios.2019.111520] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 07/02/2019] [Accepted: 07/15/2019] [Indexed: 01/23/2023]
Abstract
The excellent conductivity matching of two-dimensional (2D) semiconductor nanomaterials (e.g. MoS2) with cancer cell plays an important role in ultrasensitive label-free impedimetric detection of circulating tumor cells (CTC) (<1 cell/mL). Firstly, 2D semiconductor materials (e.g. 2D MoS2) exfoliated by folic acid (FA) is used to construct MoS2/FA-modified gold electrode (AuE/MoS2/FA). Then, the fabricated electrode is applied for HeLa cell detection in a linear range from 1 to 105 cell/mL with a detection limit of 0.43 cell/mL (S/N = 3). The detection mechanism of high sensitivity might be owing to the electric conductivity matching of MoS2 (0.14 S/m) to cancer cell (0.13-0.23 S/m). A negligible conductivity change induced by cancer cell will produce a large impedance change of semiconductor electrode. Furthermore, HeLa cells dispersed in healthy blood samples are detected by suggested cytosensor in a linear range from 50 to 105 cell/mL with a detection limit of 52.24 cell/mL (S/N = 2). Finally, we demonstrate that the cytosensor is capable of differentiating patients of cervical and liver cancers by the real CTC analysis from healthy control.
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45
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Iliescu FS, Poenar DP, Yu F, Ni M, Chan KH, Cima I, Taylor HK, Cima I, Iliescu C. Recent advances in microfluidic methods in cancer liquid biopsy. BIOMICROFLUIDICS 2019; 13:041503. [PMID: 31431816 PMCID: PMC6697033 DOI: 10.1063/1.5087690] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/24/2019] [Indexed: 05/04/2023]
Abstract
Early cancer detection, its monitoring, and therapeutical prediction are highly valuable, though extremely challenging targets in oncology. Significant progress has been made recently, resulting in a group of devices and techniques that are now capable of successfully detecting, interpreting, and monitoring cancer biomarkers in body fluids. Precise information about malignancies can be obtained from liquid biopsies by isolating and analyzing circulating tumor cells (CTCs) or nucleic acids, tumor-derived vesicles or proteins, and metabolites. The current work provides a general overview of the latest on-chip technological developments for cancer liquid biopsy. Current challenges for their translation and their application in various clinical settings are discussed. Microfluidic solutions for each set of biomarkers are compared, and a global overview of the major trends and ongoing research challenges is given. A detailed analysis of the microfluidic isolation of CTCs with recent efforts that aimed at increasing purity and capture efficiency is provided as well. Although CTCs have been the focus of a vast microfluidic research effort as the key element for obtaining relevant information, important clinical insights can also be achieved from alternative biomarkers, such as classical protein biomarkers, exosomes, or circulating-free nucleic acids. Finally, while most work has been devoted to the analysis of blood-based biomarkers, we highlight the less explored potential of urine as an ideal source of molecular cancer biomarkers for point-of-care lab-on-chip devices.
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Affiliation(s)
- Florina S. Iliescu
- School of Applied Science, Republic Polytechnic, Singapore 738964, Singapore
| | - Daniel P. Poenar
- VALENS-Centre for Bio Devices and Signal Analysis, School of EEE, Nanyang Technological University, Singapore 639798, Singapore
| | - Fang Yu
- Singapore Institute of Manufacturing Technology, A*STAR, Singapore 138634, Singapore
| | - Ming Ni
- School of Biological Sciences and Engineering, Yachay Technological University, San Miguel de Urcuquí 100105, Ecuador
| | - Kiat Hwa Chan
- Division of Science, Yale-NUS College, Singapore 138527, Singapore
| | | | - Hayden K. Taylor
- Department of Mechanical Engineering, University of California, Berkeley, California 94720, USA
| | - Igor Cima
- DKFZ-Division of Translational Oncology/Neurooncology, German Cancer Consortium (DKTK), Heidelberg and University Hospital Essen, Essen 45147, Germany
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Rapid prototyping of Nanoroughened polydimethylsiloxane surfaces for the enhancement of immunomagnetic isolation and recovery of rare tumor cells. Biomed Microdevices 2019; 21:58. [PMID: 31227909 DOI: 10.1007/s10544-019-0418-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Traditional immunomagnetic assays for the isolation and recovery of circulating tumor cells (CTCs) usually require sophisticated device or intense magnetic field to simultaneously achieve high capture efficiency and high throughout. In this study, a simple microfluidic chip featured with nanoroughened channel substrate was developed for effectively capture and release of CTCs based on an immunomagnetic chip-based approach. The nanoroughened substrate aims to increase the cell-surface contact area, facilitate the immobilization of magnet particles (MPs) and accommodate cell attachment tendency. Hep3B tumor cells were firstly conjugated with MPs that were functionalized with anti-EpCAM. Comparing with the flat channel, MPs modified tumor cells can be more effectively captured on nanoroughened substrate at the presence of the magnetic field. Upon the removal of magnetic field, these captured cells can be released from the device and collected for further analysis. Under the optimum operating conditions, the capture efficiency of tumor cells was obtained as high as ~90% with a detection limit of 10 cell per mL. Additionally, recovery rates of trapped tumor cells at various densities all exceeded 90% and their biological potencies were well retained by investigating the cell attachment and proliferation. Therefore, the present approach may potentially be used in clinical CTC analysis for cancer diagnosis and prognosis as well as the fundamental understanding of tumor metastasis.
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47
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Gribko A, Künzel J, Wünsch D, Lu Q, Nagel SM, Knauer SK, Stauber RH, Ding GB. Is small smarter? Nanomaterial-based detection and elimination of circulating tumor cells: current knowledge and perspectives. Int J Nanomedicine 2019; 14:4187-4209. [PMID: 31289440 PMCID: PMC6560927 DOI: 10.2147/ijn.s198319] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Circulating tumor cells (CTCs) are disseminated cancer cells. The occurrence and circulation of CTCs seem key for metastasis, still the major cause of cancer-associated deaths. As such, CTCs are investigated as predictive biomarkers. However, due to their rarity and heterogeneous biology, CTCs’ practical use has not made it into the clinical routine. Clearly, methods for the effective isolation and reliable detection of CTCs are urgently needed. With the development of nanotechnology, various nanosystems for CTC isolation and enrichment and CTC-targeted cancer therapy have been designed. Here, we summarize the relationship between CTCs and tumor metastasis, and describe CTCs’ unique properties hampering their effective enrichment. We comment on nanotechnology-based systems for CTC isolation and recent achievements in microfluidics and lab-on-a-chip technologies. We discuss recent advances in CTC-targeted cancer therapy exploiting the unique properties of nanomaterials. We conclude by introducing developments in CTC-directed nanosystems and other advanced technologies currently in (pre)clinical research.
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Affiliation(s)
- Alena Gribko
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Julian Künzel
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Désirée Wünsch
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Qiang Lu
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Sophie Madeleine Nagel
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Shirley K Knauer
- Department of Molecular Biology II, Center for Medical Biotechnology (ZMB)/Center for Nanointegration (CENIDE), University Duisburg-Essen, Essen 45117, Germany
| | - Roland H Stauber
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Guo-Bin Ding
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ; .,Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, People's Republic of China,
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Ruzycka M, Cimpan MR, Rios-Mondragon I, Grudzinski IP. Microfluidics for studying metastatic patterns of lung cancer. J Nanobiotechnology 2019; 17:71. [PMID: 31133019 PMCID: PMC6537392 DOI: 10.1186/s12951-019-0492-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 05/04/2019] [Indexed: 01/09/2023] Open
Abstract
The incidence of lung cancer continues to rise worldwide. Because the aggressive metastasis of lung cancer cells is the major drawback of successful therapies, the crucial challenge of modern nanomedicine is to develop diagnostic tools to map the molecular mechanisms of metastasis in lung cancer patients. In recent years, microfluidic platforms have been given much attention as tools for novel point-of-care diagnostic, an important aspect being the reconstruction of the body organs and tissues mimicking the in vivo conditions in one simple microdevice. Herein, we present the first comprehensive overview of the microfluidic systems used as innovative tools in the studies of lung cancer metastasis including single cancer cell analysis, endothelial transmigration, distant niches migration and finally neoangiogenesis. The application of the microfluidic systems to study the intercellular crosstalk between lung cancer cells and surrounding tumor microenvironment and the connection with multiple molecular signals coming from the external cellular matrix are discussed. We also focus on recent breakthrough technologies regarding lab-on-chip devices that serve as tools for detecting circulating lung cancer cells. The superiority of microfluidic systems over traditional in vitro cell-based assays with regard to modern nanosafety studies and new cancer drug design and discovery is also addressed. Finally, the current progress and future challenges regarding printable and paper-based microfluidic devices for personalized nanomedicine are summarized.
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Affiliation(s)
- Monika Ruzycka
- Department of Applied Toxicology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097, Warsaw, Poland
| | - Mihaela R Cimpan
- Biomaterials - Department for Clinical Dentistry, University of Bergen, Årstadveien 19, 5009, Bergen, Norway
| | - Ivan Rios-Mondragon
- Biomaterials - Department for Clinical Dentistry, University of Bergen, Årstadveien 19, 5009, Bergen, Norway
| | - Ireneusz P Grudzinski
- Department of Applied Toxicology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097, Warsaw, Poland.
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Sun H, Han L, Yang L, Yang Y, Jiang W, Xu T, Jia L. Modular Chamber Assembled with Cell-Replicated Surface for Capture of Cancer Cells. ACS Biomater Sci Eng 2019; 5:2647-2656. [PMID: 33405768 DOI: 10.1021/acsbiomaterials.8b01605] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The capture of circulating tumor cells (CTCs) is mainly carried out with a small volume of blood using magnetic nanoparticles and complex microfluidics. In this study, we propose a CTC-capture apparatus based on a modular design and called this apparatus as the CTC chamber. Distinct from other CTC-capture apparatuses, the capacity of the CTC chamber could be altered by varying the number of CTC-capture modules to accommodate the different volumes of blood sample. The core component of the CTC-capture module was a polydimethylsiloxane (PDMS) film with cell-replicated topological structure and anti-EpCAM antibody coating. Both synergistic roles can enhance the capture yield of cancer cells. Furthermore, the CTC chamber was assembled with one or three CTC-capture modules for the capture of cancer cells from spiked blood samples representing late-stage (3 mL of blood, 10 cancer cells mL-1) or middle-early stage (9 mL of blood, 1 cancer cell mL-1) cancer. The results showed that high capture yield (EpCAM-positive, ∼80%; EpCAM-negative, ∼65%) and purity (EpCAM-positive, ∼90%; EpCAM-negative, ∼80%) could be obtained within 1 h. This economic and facile CTC chamber could therefore open up opportunities for designing the next-generation CTC detection devices suitable for the diagnosis of different stages of cancer.
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Affiliation(s)
- He Sun
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116023, P. R. China
| | - Lulu Han
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116023, P. R. China
| | - Liwei Yang
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116023, P. R. China
| | - Yan Yang
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116023, P. R. China
| | - Wenning Jiang
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116023, P. R. China
| | - Ting Xu
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116023, P. R. China
| | - Lingyun Jia
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116023, P. R. China
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Rostami P, Kashaninejad N, Moshksayan K, Saidi MS, Firoozabadi B, Nguyen NT. Novel approaches in cancer management with circulating tumor cell clusters. JOURNAL OF SCIENCE: ADVANCED MATERIALS AND DEVICES 2019; 4:1-18. [DOI: 10.1016/j.jsamd.2019.01.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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