Noninvasive prenatal diagnosis targeting fetal nucleated red blood cells

Abstract

Noninvasive prenatal diagnosis (NIPD) aims to detect fetal-related genetic disorders before birth by detecting markers in the peripheral blood of pregnant women, holding the potential in reducing the risk of fetal birth defects. Fetal-nucleated red blood cells (fNRBCs) can be used as biomarkers for NIPD, given their remarkable nature of carrying the entire genetic information of the fetus. Here, we review recent advances in NIPD technologies based on the isolation and analysis of fNRBCs. Conventional cell separation methods rely primarily on physical properties and surface antigens of fNRBCs, such as density gradient centrifugation, fluorescence-activated cell sorting, and magnetic-activated cell sorting. Due to the limitations of sensitivity and purity in Conventional methods, separation techniques based on micro-/nanomaterials have been developed as novel methods for isolating and enriching fNRBCs. We also discuss emerging methods based on microfluidic chips and nanostructured substrates for static and dynamic isolation of fNRBCs. Additionally, we introduce the identification techniques of fNRBCs and address the potential clinical diagnostic values of fNRBCs. Finally, we highlight the challenges and the future directions of fNRBCs as treatment guidelines in NIPD. Graphical Abstract

High-Density Microporous Drainage-Integrating Sheath Flow Generator for Streamlining Microfluidic Cell Sorting Systems

“…Selection of specific cells from complex biological samples using microfluidic technologies has been intensively studied over the past decades, and many new principles for continuous cell sorting have been devised. − The sorting targets of biological samples subjected to microfluidics are not limited to cells but vary from submicrometer-sized extracellular vesicles to large cell clusters or living organisms. Representative applications of microfluidic cell sorters include the detection of rare cells as disease markers, , sorting of highly potent stem cells, , and subpopulation characterization of specific cell populations . In particular, the isolation of circulating tumor cells (CTCs) from blood samples assisted by microengineered structures has proven to be significantly useful for early tumor diagnosis and evaluation of antitumor drug efficacy. , Various physicochemical properties of cells have been utilized for sorting, including size, density, deformability, and surface markers.…”

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“…Moreover, antiplatelet medications could inhibit thrombi by reducing platelet aggregation and bioactivation, which helps avoid secondary embolisms from thrombus fragments. To test our hypothesis, a carrier assembled using hydrophobic DIP and the hydrophobic conductive polymer, PPy [ 27 – 30 ], was intricately engineered. The intermolecular forces and interactions were anticipated to drive the co-assembly of DIP and PPy.…”

Aptamer-Mediated Enrichment of Rare Circulating Fetal Nucleated Red Blood Cells for Noninvasive Prenatal Diagnosis

“…In addition to high-throughput sequencing of cffDNA fragments, circulating fetal cells containing intact genome information with high purity provide another promising target for noninvasive genetic diagnosis. − So far, different kinds of fetal cells, including trophoblast cells, hematopoietic progenitor cells, fetal lymphocytes, and fetal NRBCs, have been identified in maternal circulation. ,, Among them, fNRBCs have advantages such as fetal rather than placental origin and short lifetime during maternal circulation, making them an optimal target for cell-based NIPT. − With the advancement of single-cell genetic analysis, the development of reliable strategies for rare circulating fetal cell enrichment from maternal peripheral blood remains one of the biggest obstacles to the clinical translation of cfNRBC-based NIPT. In past decades, different fetal cell enrichment technologies have been developed based on their biochemical or biophysical properties, such as magnetic- or fluorescence-activated cell sorting, , microfluidics, − dielectrophoresis, and cell size-based isolation .…”