A hydrogel-based mechanical metamaterial for the interferometric profiling of extracellular vesicles in patient samples

The utility of mechanical metamaterials for biomedical applications has seldom been explored. Researchers from the National University of Singapore show that a metamaterial that is mechanically responsive to antibody-mediated biorecognition can serve as an optical interferometric mask to molecularly profile extracellular vesicles in ascites fluid from patients with cancer. The metamaterial consists of a hydrogel responsive to temperature and redox activity functionalized with antibodies to surface biomarkers on extracellular vesicles, and is patterned into micrometric squares on a gold-coated glass substrate. Through plasmonic heating, the metamaterial is maintained in a transition state between a relaxed form and a buckled state. Binding of extracellular vesicles from the patient samples to the antibodies on the hydrogel causes it to undergo crosslinking, induced by free radicals generated via the activity of horseradish peroxidase conjugated to the antibodies. Hydrogel crosslinking causes the metamaterial to undergo fast chiral re-organization, inducing amplified changes in its mechanical deformation and diffraction patterns, which are detectable by a smartphone camera. The mechanical metamaterial may find broad utility in the sensitive optical immunodetection of biomolecules.

Critically locked mechanical metamaterial for amplified molecular profiling

Fig. 1

a, Schematic of the MORPH system. The technology is designed to enhance the hydrogel’s responsiveness to biomolecular stimuli. Dual-responsive hydrogel, which comprises NIPAM as the temperature-responsive monomer, NATA as the redox-responsive monomer and antibody monomer for molecular recognition, is patterned into square-hole lattices on a gold-coated glass (Au-SiO2) substrate. The patterned metamaterial is then precisely locked to its critical transition state through LED-activated plasmonic heating at the gold–hydrogel interface. When target biomarkers are introduced, free radicals are generated through antibody-peroxidase activity to induce further hydrogel crosslinking. This mechanical perturbation rapidly breaks the transition state and triggers a dramatic chiral transformation of the metamaterial, leading to amplified changes in the projected optical diffraction. b, Metamaterial deformations and optical signals. When the metamaterial is unlocked, biomarker-induced swelling induces only minimal deformations, and thus the optical diffraction signal is small. However, when the metamaterial is critically locked (near its critical point, CP), an equal amount of biomarker-induced swelling triggers the rapid release of the accumulated strain energy and induces a dramatic chiral pattern transformation. This geometric re-organization causes a distinct mode change in the projected diffraction pattern, thereby enabling amplified optical detection of even scarce biomolecules. c, Photograph of the microfluidic device. d,e, Photograph (d) and optical path diagram (e) of the smartphone-based detector. The miniaturized microfluidic system and optical detector are designed to streamline the MORPH assay workflow and facilitate optical diffraction measurements. Scale bar, 1 cm.

Zhao H, Pan S, Natalia A, Wu X, Ong CJ, Teo MCC, So JBY, Shao H. (2022) A hydrogel-based mechanical metamaterial for the interferometric profiling of extracellular vesicles in patient samples. Nat Biomed Eng [Epub ahead of print]. [abstract]

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