Challenges and Solutions in Developing Ultrasensitive Biosensors

Abstract

This Perspective focuses on the latest strategies and challenges for the development of bioanalytical sensors with sub-picomolar detection limits. Achieving sub-picomolar detection limits has three major challenges: (1) assay sensitivity, (2) response time, and (3) selectivity (including limiting background signals). Each of these challenges is discussed, along with how nanomaterials provide the solutions. One strategy to gain greater sensitivity involves confining the sensing volume to the nanoscale, as used in nanopore- or nanoparticle-based sensors, because nanoparticles are ubiquitous in amplification. Methods to improve response time typically focus on obtaining an intimate mixture between the sensor and the sample either by extending the length scale of nanoscale sensors using nanostructuring or by dispersing magnetic nanoparticles through the sample to capture the analyte. Loading nanoparticles with many biorecognition species is one solution to help address the challenge of selectivity. Many examples in this Perspective explore the detection of prostate-specific antigen which enables a comparison between strategies. Finally, exciting future opportunities in developing single-molecule sensors and the requirements to go even lower in concentration are explored.

How Nanoparticles Transform Single Molecule Measurements into Quantitative Sensors

“…Many of the challenges faced with single molecule quantitative sensors are solved with judicious design of the nanoparticles employed in these sensors. For example, the slow response times that nanoscale sensors, which rely on diffusion alone, suffer from at biologically relevant concentrations of analytes in a range of 10 −12 to 100 × 10 −18 m can be solved using magnetic nanoparticles that are brought to the sensing surface under a magnetic field . Similarly, many receptors on a nanoparticle address the issue of lifetime of biomolecular pairs.…”

“…Generally, single molecule measurements may be accomplished by serial detection of single molecules or by measurement of many single molecules in parallel. In the serial approach, many individual single molecules must be counted one at a time as they singly pass through the measurement volume . So the response time issue is exacerbated.…”

Nanomaterials for molecular signal amplification in electrochemical nucleic acid biosensing: recent advances and future prospects for point-of-care diagnostics

“…Indeed, the sensor response will not reflect the measurement of an ensemble of bound molecules but is triggered by individual binding events. 38,39 Accordingly, the measurement time plays a crucial role when probing ultra-low concentrations, as this will be strongly influenced by the surface coverage of analytes and the capturing elements on the surfaces. Calculations by Sheehan and Whitman 40 suggest that concentration detection limits within the femtomolar range are limited by mass transport, which may require hours or even days for the analyte molecules to diffuse to the electrode surface.…”

The Growing Impact of Micro/Nanomaterial‐Based Systems in Precision Oncology: Translating “Multiomics” Technologies

“…The preparation of well-defined structures and materials at the micro/nanoscale has considerable potential in cancer diagnostics due to exceptional detection sensitivity, specificity, and response time for target molecules of equivalent scale. [58] Specifically, this section reviews the advancements in miniature material-based systems which can directly affect detection performance by enhancing signals, minimizing nonspecific binding, and accelerating response time.…”