Ultrasound-sensitive and label-free detection of the chirality of diabetes-related metabolic molecules

March 30, 2021

(Nanowerk Spotlight) Chirality is a critical concept in chemistry and life sciences, especially when applied at the molecular level. Many molecules such as amino acids, proteins, sugars, and DNA are chiral. Two mirror images of a chiral molecule are called enantiomers or optical isomers. Pairs of enantiomers are often referred to as right-handed and left-handed.

“Abnormal concentrations of chiral molecules have been observed in people with age and various chronic diseases such as cancer, diabetes, kidney disease and neurological diseases, suggesting the potential for using chiral biomarkers as health indicators for diagnostic and prognostic applications.” Yuebing Zheng, Associate Professor and William W. Hagerty Scholarship in Engineering at the University of Texas at Austin, tells Nanowerk. “In particular, elevated levels of many D-type metabolic molecules in the urine have shown a strong correlation with diabetes mellitus.”

The change in the chirality of urinary metabolites caused by diabetes has not been fully studied, which hinders the clinical development of diagnosis and monitoring of diseases on a chirality basis. In particular, establishing an accurate relationship between diabetes and urinary metabolite chirality is critical to improving knowledge of the pathological roles of the chiral disorder, which will facilitate the development of new diagnostic tools.

However, up to now it has been very difficult to determine the chirality of urine metabolites quickly and with high accuracy.

A new method developed by Zheng’s group and described in ACS Nano (“Label-Free Ultrasensitive Detection of Abnormal Chiral Metabolites in Diabetes”) addresses the challenges of chiral metabolite detection through the use of microbubble-induced intense accumulation of Biomolecules based on plasmonic chiralism cope with metamaterials with high sensitivity (100 pM) and low volume (10 µL).

“We demonstrated label-free chiral detection of metabolic molecules at the picomolar level by microbubble-induced rapid accumulation of biomolecules on plasmonic chiral sensors, showing a 10 million-fold improvement in sensitivity compared to prior art plasmonic chiral sensors,” says Yaoran Liu, a graduate student in Zheng’s group and the newspaper’s first author. “With its ultra-high sensitivity, our technique reveals the typically undetectable diabetes-induced abnormal clockwise shift in the overall chirality of urinary metabolites.”

The team shows that monitoring such abnormal shifts in overall chirality enables a diagnostic accuracy of 84%, a large improvement compared to 72% for conventional glucose tests on clinical urine samples. a) Schematic representation of the collection and purification of urine samples and the microbubbles that allowed the accumulation of chiral metabolic molecules on the chiral metasurface to improve chiral perception and detection of diabetics; b) Normalized dissymmetry factors (ΔΔλ / λ)total) measured on urine from normal and diabetic people; c) Operating characteristics of the receiver (ROC) of ΔΔλ / λtotal and glucose concentration. (Image: Zheng Research Group, University of Texas, Austin) (click the image to enlarge)

“So far, conventional chiroptical methods have suffered from high sample consumption and low molar sensitivity for metabolic molecules with ultra-small molecular mass and weak interactions between light and matter, which hinders their application in the detection of traces of chiral metabolites in urine,” emphasizes Liu.

Although plasmon-enhanced chiral sensors can distinguish chiral molecules at the picogram level with a wide range of molecular weights, the lowest detectable analyte concentration has been limited to ~ 1 mM in order to ensure sufficient molecule-metamaterial interactions, which hinders the chiral detection of trace urine metabolomes in clinical applications.

In addition, plasmonic chiral scanning requires that the analytes be physically adsorbed on the plasmonic surfaces or be close to the superchiral fields with short working distances (ie, in the nanometer range).

The researchers achieved their ultra-high sensitivity in chiral detection of biomolecules through the use of two enhancement mechanisms: the microbubble-induced accumulation of biomolecules on the chiral plasmonic substrates; and the subsequent plasmon-enhanced chiral perception.

The plasmonic substrate used is based on previous work by Zheng’s group on plasmonic chiral moiré metamaterials (read our previous Nanowork Spotlight on this work: “A new type of ultra-thin plasmonic chiral metamaterial”). In the present work they apply this metamaterial, which consists of two layers of gold nano-hole arrays that are stacked in moiré patterns to generate both the optothermal microbubbles and the superchiral fields.

Liu explains the working principle of this technique: “Irradiating a focused laser onto the metamaterial induces plasmon-enhanced optical heating at the laser focus point, evaporates the solution above the substrate and creates a microbubble. The microbubble-induced Marangoni convection can be effective in pulling biomolecules into the Solution in the direction of the laser spot. ”

“The increased concentration of molecules near the substrate – in a range of about 5 µm2 – and the strong downward forces in the stagnation area near the microbubble-substrate interfaces then effectively print the molecules onto the plasmonic substrate with high binding affinity, allowing effective molecule accumulation for increased sensitivity, “he adds.

The team is currently working on improving specificity through improved filtering or the integration of microfluidic separation techniques. They also use this technique to predict chronic kidney disease.

“Accumulation-assisted plasmonic chiral sensing shows great potential in the development of point-of-care devices for first-line non-invasive screening and the prognosis of pre-diabetes or early-stage diabetes and its complications,” concludes Zheng. “Since chiral molecules have been found to be altered in various chronic diseases such as arteriosclerosis, neurodegenerative diseases and cancers, we envision routine chiral detection that is sensitive, non-invasive and can also be used as a new tool for the early detection of chronic diseases . ”

The main problem in the team’s current technology is separating the molecules of interest from the complex biological solution. However, they are confident that the combination of the current chiral detection technology with the multiplexing module for chiral separation may enable the specific detection of chiral biomarkers at the trace level in complex human biofluidics for the detection of diseases.

Michael is the author of three books for the Royal Society of Chemistry: Nano-Society: Pushing the Boundaries of Technology, Nanotechnology: The Future Is Tiny, and Nanoengineering: The Skills and Tools That Make Technology Invisible Copyright ©


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