Abstract
Performing chemical analysis at the nanoliter (nL) scale is of paramount importance for medicine, drug development, toxicology, and research. Despite the numerous methodologies available, a tool for obtaining chemical information non-invasively is still missing at this scale. Observer effects, sample destruction and complex preparatory procedures remain a necessary compromise. Among non-invasive spectroscopic techniques, one able to provide holistic and highly resolved chemical information in-vivo is nuclear magnetic resonance (NMR). For its renowned informative power and ability to foster discoveries and life-saving applications, efficient NMR at microscopic scales is highly sought after, but so far technical limitations could not match the stringent necessities of microbiology, such as biocompatible handling, ease of use, and high throughput. Here we introduce a novel microsystem, which combines CMOS technology with 3D microfabrication, enabling nL NMR as a platform tool for non-invasive spectroscopy of organoids, 3D cell cultures, and early stage embryos. In this study we show its application to microlivers models simulating non-alcoholic fatty liver disease, demonstrating detection of lipid metabolism dynamics in a time frame of 14 days based on 117 measurements of single 3D human liver microtissues.
Highlights
Performing chemical analysis at the nanoliter scale is of paramount importance for medicine, drug development, toxicology, and research
In this study we focus on human liver MTs, treated to simulate non-alcoholic fatty liver disease (NAFLD)[17,18]
MTs are exposed to different dietary regimes: a fasting diet is used to culture the livers in a lean state, while a diabetic diet induces steatosis
Summary
Performing chemical analysis at the nanoliter (nL) scale is of paramount importance for medicine, drug development, toxicology, and research. NMR spectroscopy of eggs of microorganisms having a volume of just 0.1 nL was reported in a relatively weak field strength of 7 T Such advancement was possible thanks to a novel approach based on complementary metal-oxide semiconductor (CMOS) microchips that delivered high sensitivity, robustness, and a local and accessible sensing region[15]. In this work we present an innovative device that combines the advantages of CMOS-based NMR probes with an unprecedented ease of use, allowing investigations of nL biological entities with a satisfactory statistic for the first time To show these capabilities, we here describe a first study using nL NMR on 3D microtissues (MTs), microscopic cell aggregates that mimic features and functionalities of their macroscopic counterparts. In this study we successfully utilize NMR spectroscopy on single liver MTs and demonstrate the observation of a dynamic fatty acid metabolism associated to a diet switch inducing recovery from a steatotic condition
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