Urinary MicroRNA-Based Diagnostic Model for Central Nervous System Tumors Using Nanowire Scaffolds

Abstract

There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood–brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.

Liquid Biopsy and Primary Brain Tumors

“…Upregulation of miR-21 may serve as an early diagnostic but also as prognostic [ 63 ] and monitoring marker [ 81 ], whereas panels of different miRNAs were found to be potential markers for diagnostics and tumor grade, as well as prognostics [ 82 ]. In an elegant new model, urine samples from mainly glioma patients and noncancer individuals were used to develop with artificial intelligence (AI) a diagnostic model for the detection of such tumors in urine samples [ 83 ]. A panel of 23 miRNAs was found to separate noncancerous from glioma patients.…”

Oxide nanowire microfluidics addressing previously-unattainable analytical methods for biomolecules towards liquid biopsy

“…In one of our most recent papers, we developed a sterilizable and mass-producible nanowire-based device to help in meeting the longterm goal of achieving liquid biopsy using urinary miRNAs. 56 An assembly-type microfluidic nanowire device was fabricated by two processes: first, ZnO nanowire scaffolds were fabricated on a silicon substrate, and second, ZnO nanowire scaffolds were assembled in an assembly-type microfluidic device (Fig. 4).…”

“…4 (a) Schematic of miRNA extraction in urine. 55,56 (b-d) Schematic and SEM images for nanowire microfluidics to extract miRNAs from urine. 55 (e) Exploded view of the assembly-type of nanowire microfluidics consisting of PEEK tubes, stainless steel holders, a COP resin microfluidic substrate, nanowires on a Si substrate, and a COP resin substrate.…”

“…55 (e) Exploded view of the assembly-type of nanowire microfluidics consisting of PEEK tubes, stainless steel holders, a COP resin microfluidic substrate, nanowires on a Si substrate, and a COP resin substrate. 56 (f) Schematic of miRNA extraction from urine using the assembly-type of nanowire microfluidics. 56…”

“…56 (f) Schematic of miRNA extraction from urine using the assembly-type of nanowire microfluidics. 56…”