Whole-Blood Boundary Analysis of BioFET-Based ctDNA Detection for Intravascular Sensing in Intrabody Nanonetworks

TL;DR

This study models the limitations of BioFET nanosensors for detecting circulating tumor DNA in whole blood, highlighting key factors that affect detection reliability in intravascular sensing applications.

Contribution

It introduces a reduced-order stochastic simulation model to analyze the boundary conditions for reliable ctDNA detection using BioFET sensors in blood.

Findings

Short Debye length and nanometer charge-to-channel separation attenuate current shifts.

Background noise and fluctuations reduce the detection margin.

Simulations show current shifts often do not exceed blank thresholds at low ctDNA levels.

Abstract

Liquid biopsy can detect tumor-derived biomarkers such as circulating tumor DNA (ctDNA), but ultra-low-fraction assays remain costly, slow, and difficult to scale. This motivates interest in intravascular in vivo sensing in the context of intrabody nanonetworks, where nanosensors could support local biomarker monitoring. BioFET-based nanosensors are relevant here because they are label-free, highly miniaturizable, and have shown strong ctDNA sensitivity in controlled media. We examine whether this sensitivity still yields reliable ctDNA detection in whole blood using a reduced-order stochastic simulation model that links operating-point selection, Debye-screened charge transduction, stochastic finite-capacity binding, nonspecific adsorption, background fluctuations, and intrinsic electronic noise to blank-threshold detection. Monte Carlo evaluation with physiologically grounded parameters shows that short Debye length and several-nanometer charge-to-channel separation attenuate the current shift, while low-frequency noise and background fluctuations reduce the margin between target-present and blank responses. Under the tested quasi-static charge-gating regime, the simulated current shifts do not reliably exceed the blank-derived threshold at low ctDNA concentrations. The model therefore provides a whole-blood boundary analysis that identifies which interface configurations and operating conditions most strongly limit reliable BioFET-based intravascular ctDNA detection.