Abstract
Hyaluronan (or hyaluronic acid, HA) is a ubiquitous molecule that plays critical roles in numerous physiological functions in vivo, including tissue hydration, inflammation, and joint lubrication. Both the abundance and size distribution of HA in biological fluids are recognized as robust indicators of various pathologies and disease progressions. However, such analyses remain challenging because conventional methods are not sufficiently sensitive, have limited dynamic range, and/or are only semi-quantitative. Here we demonstrate label-free detection and molecular weight discrimination of HA with a solid-state nanopore sensor. We first employ synthetic HA polymers to validate the measurement approach and then use the platform to determine the size distribution of as little as 10 ng of HA extracted directly from synovial fluid in an equine model of osteoarthritis. Our results establish a quantitative method for assessment of a significant molecular biomarker that bridges a gap in the current state of the art.
Highlights
Hyaluronan is a ubiquitous molecule that plays critical roles in numerous physiological functions in vivo, including tissue hydration, inflammation, and joint lubrication
As an initial assessment of the utility of SS-nanopores to probe HA, we first conducted a set of experiments using a polydisperse mixture of HA isolated from Streptococcus zooepidemicus fermentation (Methods section)
While event durations have typically been more correlated with molecular weight (MW) than depth in previous reports[27], signal variations of this kind could skew the data, since folded molecules translocate more rapidly than unfolded ones
Summary
Hyaluronan (or hyaluronic acid, HA) is a ubiquitous molecule that plays critical roles in numerous physiological functions in vivo, including tissue hydration, inflammation, and joint lubrication Both the abundance and size distribution of HA in biological fluids are recognized as robust indicators of various pathologies and disease progressions. High-MW HA is far more responsible than lowMW HA for the lubricating properties of synovial fluid Both the abundance and size distribution of HA are important biomarkers for disease pathologies and are essential to understanding the immunomodulatory and joint lubrication roles of HA in vivo. As a result of these considerations, the most widely used HA assessment approach is agarose or polyacrylamide gel electrophoresis[16,17], through which band intensity and position can be analyzed to denote a size distribution This method is slow, requires large sample size (fluid volume and HA mass), requires calibrated standards The dynamic range of that system is very narrow; direct assessment was limited to small HA (
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