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

ABSTRACT The utility of mechanical metamaterials for biomedical applications has seldom been explored. Here we 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. Access through your institution Buy or subscribe This is

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FOR NON-INVASIVE IMAGING OF TISSUE MECHANICS IN VIVO Article Open access 16 October 2023 IMAGING-BASED SPECTROMETER-LESS OPTOFLUIDIC BIOSENSORS BASED ON DIELECTRIC METASURFACES FOR DETECTING

EXTRACELLULAR VESICLES Article Open access 31 May 2021 SINGLE-CELL AND EXTRACELLULAR NANO-VESICLES BIOSENSING THROUGH PHASE SPECTRAL ANALYSIS OF OPTICAL FIBER TWEEZERS BACK-SCATTERING

SIGNALS Article Open access 10 July 2024 DATA AVAILABILITY The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and

analyzed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request. CODE

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thank X. Qiu, J.W.S. Tan, C.Y.J. Chee and S.C. Teo for assistance with clinical-sample collection. This work was supported in part by funding from the National University of Singapore (NUS),

the NUS Research Scholarship, the Ministry of Education, the National Medical Research Council and the Institute for Health Innovation & Technology, and by an IMCB Independent

Fellowship and a NUS Early Career Research Award. AUTHOR INFORMATION Author notes * These authors contributed equally: Haitao Zhao, Sijun Pan. AUTHORS AND AFFILIATIONS * Institute for Health

Innovation & Technology, National University of Singapore, Singapore, Singapore Haitao Zhao, Sijun Pan, Auginia Natalia, Xingjie Wu & Huilin Shao * Department of Biomedical

Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore Auginia Natalia & Huilin Shao * Division of Surgical Oncology, National Cancer Centre,

Singapore, Singapore Chin-Ann J. Ong & Melissa C. C. Teo * Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Jimmy B. Y. So 

& Huilin Shao * Division of Surgical Oncology, National University Cancer Institute, Singapore, Singapore Jimmy B. Y. So * Institute of Molecular and Cell Biology, Agency for Science,

Technology and Research, Singapore, Singapore Huilin Shao Authors * Haitao Zhao View author publications You can also search for this author inPubMed Google Scholar * Sijun Pan View author

publications You can also search for this author inPubMed Google Scholar * Auginia Natalia View author publications You can also search for this author inPubMed Google Scholar * Xingjie Wu

View author publications You can also search for this author inPubMed Google Scholar * Chin-Ann J. Ong View author publications You can also search for this author inPubMed Google Scholar *

Melissa C. C. Teo View author publications You can also search for this author inPubMed Google Scholar * Jimmy B. Y. So View author publications You can also search for this author inPubMed 

Google Scholar * Huilin Shao View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS H.Z., S.P. and H.S. designed the study. C.-A.J.O., M.C.C.T.

and J.B.Y.S. provided de-identified clinical samples and health information. H.Z., S.P., X.W. and A.N. performed the research. H.Z., S.P., A.N. and H.S. analyzed the data and wrote the

manuscript. All authors contributed to revising the manuscript. CORRESPONDING AUTHOR Correspondence to Huilin Shao. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Biomedical Engineering_ thanks Giuseppe Strangi and the other, anonymous, reviewer(s) for their contribution to the peer review of this

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the interferometric profiling of extracellular vesicles in patient samples. _Nat. Biomed. Eng_ 7, 135–148 (2023). https://doi.org/10.1038/s41551-022-00954-7 Download citation * Received: 30

October 2020 * Accepted: 15 September 2022 * Published: 27 October 2022 * Issue Date: February 2023 * DOI: https://doi.org/10.1038/s41551-022-00954-7 SHARE THIS ARTICLE Anyone you share the

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