Advances in screening and diagnostic lab-on-chip tools for gynaecological cancers – a review

Figures & data

Figure 1. Layouts of lab-on-chip (LoC) devices in development for gynaecological cancer detection. (a) Schematic of gold nanoparticles on a self-assembled monolayer (SAM) interdigitated electrode-based microfluidic biosensor for immunocapture of CA125 [37]; (b) construction of aptamer-linked magnetic nanoclusters and circulating tumor cell capture with biomimetic microfluidic system [38]; (c, i) integrated microfluidic chip (IMC) illustration for cell-free DNA (cfDNA) capture; (c, ii) design of the IMC for cfDNA capture [39]; (d) ExoSearch chip for continuous mixing, isolation and in situ, multiplexed detection of circulating exosomes; (d i, ii) bright-field microscope images of immunomagnetic beads manipulated in microfluidic channel for mixing and isolation of exosomes; (d iii) exosome-bound immunomagnetic beads aggregated in a microchamber with on/off switchable magnet for continuous collection and release of exosomes; (d iv) TEM image of exosome-bound immunomagnetic bead in a cross-sectional view [40].

Table 1. List of lab-on-a-chip devices to detect gynaecological cancer biomarkers using microfluidic technology.

Biomarker (associated cancer)	Associated cancer type	Device name	Method of capture	Detection method	Validation sample	Operation and performance	Ref.
CA125^a	Ovarian cancer	N/A	Gold nanoparticles coated with anti-CA125 antibodies (Figure 1(a))	Capacitance	CA125 antigens (5 μL)	Higher capacitance signal in higher concentration of CA125 antigens and lower hertz frequency. Flow rate: 0.2 μL.s^–1	Nunna et al. [37]
CA125^a	Ovarian cancer	μPAD	Gold nanoparticles coated with anti-CA125 antibodies	Electrochemical	CA125 antigens (10 μL)	LOD: 0.78 U.mL^–1	Bahavarnia et al. [45]
EpCAM^a	Ovarian cancer	N/A	Anti-EpCAM antibodies immobilized on gold surfaces and gold microfluidic channels	Fluorescence	Blood	Cell capture efficiency: 97%. Flow rate: 0.34 mL.h^–1	Cetin et al. [46]
EpCAM^a	Ovarian cancer	Biomimetic microfluidic system (BMS)	Nanosized magnetic clusters coated with EpCAM-specific aptamers. The beads were also camouflaged with leukocyte cell fragments to inhibit non-specific binding to other EpCAM-expressing leukocytes, maximizing specificity for EpCAM-expressing CTC capture (Figure 1(b))	Fluorescence	MCF-7 cells in whole blood (20 μL)	EpCAM-expressing CTC capture efficiency: >90%; time: 20 min.	Zhang et al. [38]
EpCAM^a	Ovarian cancer	CTC-chip	Anti-EpCAM antibodies on micropole structures	Fluorescence	Cell lines PC-9 and ACC-MESO-4 suspended in blood (1 mL)	Flow rate: 1.0 mL.h^–1; cell capture: 88%	Chikaishi et al. [47]
HE4^a	Ovarian cancer	N/A	Anti-HE4 antibodies on zinc-based arrays in microchannels	Fluorescence	HE4 solution	LOD: 9.3 fM	Zhao et al. [48]
CEA^a	Cervical cancer	N/A	Anti-CEA antibodies amino functional graphene (NH2-G)/thionine (Thi)/gold nanoparticles (AuNPs) nanocomposites	Electrochemical	Blood serum	LOD: 10 pg.mL^–1	Wang et al. [49]
AFP^a	Ovarian cancer	N/A	Primary anti-AFP antibodies and secondary HRP-conjugated antibodies in microchannels	Chemiluminescence	AFP solution	LOD: 21.84 ng.mL^–1	Fan et al. [50]
HPV^a	Cervical cancer	CARD	Microarray with HPV probes	Visual (CCD camera)	Cervical cells (from cervical swabs)	LOD: 10^3; copies.mL^–1 of HPV plasmids	Wang et al. [51]
BRCA1^b	Ovarian cancer	N/A	cfDNA-probe-coated magnetic beads (Figure 1(c))	Fluorescence	Plasma sample (200 μL)	Capture efficiency: 76%; time: 45 min; LOD: 25 copies	Cheng et al. [39]

CA125: cancer antigen 125; EPCAM: epithelial cell adhesion molecule; HE4: human epididymis protein 4; CEA: carcinoembryonic antigen; AFP: alpha fetoprotein; BRCA1: BReast CAncer gene 1; MCF-7: Michigan Cancer Foundation-7; PC-9: lung adenocarcinoma cell line; ACC MESO-4: human mesothelioma cell line; LOD: limit of detection; CTC: circulating tumour cells; cell-free DNA (cfDNA); NPs: nanoparticles; HRP: horse radish peroxidase; HPV: human papilloma virus; CCD: closed circuit device.

^a Protein.

^b Gene/genetic material.

Table 2. List of multiplex microfluidic LoCs for detection of gynaecological cancer biomarkers.

Biomarker	Cancer type	Device name	Method of capture and signal	Signal	Sample	Performance	Ref.
CA125^a EpCAM^a CD24^a	Ovarian cancer	ExoSearch	Magnetic beads coated with exosome-specific antibodies for exosome capture and then exposed to ovarian cancer biomarker specific antibodies	Fluorescence	Blood plasma (20 μL to 10 mL)	LOD: 7.5 × 10^5 Flow rate: 50 nL.min^–1 Exosome capture affinity: ∼100%	Zhao et al. [40] (Figure 1(d))
CA125^a AFP^a CEA^a	Ovarian cancer	N/A	Chip electrophoresis for simultaneous fluorometric aptasensing. Aptamers specific to target biomarkers bound to magnetic beads. Fluorescently labelled ssDNA primers bind to biomarker-bead complexes and emit signal.	Fluorescence	Blood serum (20 μL)	LOD: 0.15 pg.mL^–1 (CA125), 0.1 pg.mL^–1 (AFP), 0.2 pg.mL^–1 (CEA)	Xie et al. [79]
CA125^a AFP^a CEA^a	Ovarian cancer	N/A	Biomarkers interacting with HRP-conjugated antibodies covalently bound to Epoxy glass slide.	Chemiluminescence	Blood serum (200 μL)	LOD: 18.617 U.mL^–1 (CA125), 0.303 ng.mL^–1 (AFP), 1.870 ng.mL^–1 (CEA). Varying flow rates: 10–50 μL.s^–1 Run time: 40 min	Li et al. [78]
CA125^a HE4^a MMP7^a CA72-4^a	Ovarian cancer	Programmable bio-nano-chip (p-BNC)	Bead-based immunoanalyser system	Fluorescence	Blood serum (50 μL)	LOD: 1.8 U.mL^–1 (CA125), 2.3 pM (HE4), 0.2 ng.mL^–1 (MMP-7), 1.7 U.mL^–1 (CA72-4) 68.7% sensitivity at 80% specificity Run time: 43 min	McRae et al. [53]
CA125^a HE4^a OPN^a MSLN^a Hsp70^a CA153^a AFP^a IL-6^a IL-8^a	Ovarian cancer	N/A	Multi-biomarker detection with antibodies	Fluorescence	Blood serum (2 μL)	Lowest LOD: 1 pg.mL^–1 and 0.01 U.mL^–1 Run time: 30 min. Prediction rate: 91%	Wu et al. [54]
SCC^a CEA^a	Cervical cancer	N/A	Anti-SCC and anti-CEA antibody-coated SERS tags on Au@SiO2 arrays	Fluorescence	Blood serum (10 μL)	LOD: 0.45 pg.mL^–1 (SCC) and 0.36 pg.mL^–1 (CEA)	Li et al. [64]

CA125: cancer antigen 125; EPCAM: epithelial cell adhesion molecule; AFP: alpha-fetoprotein; CEA: carcinoembryonic antigen; HE4: human epididymis protein 4; MMP7: matrix metalloproteinase 7; CA72-4: cancer antigen 72-4; OPN: osteopontin; MSLN: mesothelin; HSP70: heat shock protein 70; IL-6: interleukin-6; IL-7: interleukin-7; LOD: limit of detection.

^a Protein.

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Data availability statement

Not applicable.