High Temporal Resolution Detection of Patient-Specific Glucose Uptake from Human ex Vivo Adipose Tissue On-Chip

Abstract

Human tissue in vitro models on-chip are highly desirable to dissect the complexity of a physio-pathological in vivo response because of their advantages compared to traditional static culture systems in terms of high control of microenvironmental conditions, including accurate perturbations and high temporal resolution analyses of medium outflow. Human adipose tissue (hAT) is a key player in metabolic disorders, such as Type 2 Diabetes Mellitus (T2DM). It is involved in the overall energy homeostasis not only as passive energy storage but also as an important metabolic regulator. Here, we aim at developing a large scale microfluidic platform for generating high temporal resolution of glucose uptake profiles, and consequently insulin sensitivity, under physio-pathological stimulations in ex vivo adipose tissues from nondiabetic and T2DM individuals. A multiscale mathematical model that integrates fluid dynamics and an intracellular insulin signaling pathway description was used for assisting microfluidic design in order to maximize measurement accuracy of tissue metabolic activity in response to perturbations. An automated microfluidic injection system was included on-chip for performing precise dynamic biochemical stimulations. The temporal evolution of culture conditions could be monitored for days, before and after perturbation, measuring glucose concentration in the outflow with high temporal resolution. As a proof of concept for detection of insulin resistance, we measured insulin-dependent glucose uptake by hAT from nondiabetic and T2DM subjects, mimicking the postprandial response. The system presented thus represents an important tool in dissecting the role of single tissues, such as hAT, in the complex interwoven picture of metabolic diseases.

Maintenance of Head and Neck Tumor On-Chip: Gateway to Personalized Treatment?

“…This is in agreement with previous studies from the group, using both rat liver and HNSCC tissue [38,39] and those of others who used H&E to demonstrate maintenance of tissue-specific structures including single hair follicular units and human adipose tissue [32,34] with culture times in microfluidic devices ranging from 1 to 14 days.…”

“…Further variation is also seen within tumors, (intraheterogeneity: [41,43,44]) which could in part explain the variation seen between the preculture and post-48-h microfluidic culture conditions. The use of other metabolic activity assays, similar to MTS, as a surrogate for proliferation has been used by others (MTT assay); to compare human adipose tissue before and after 7 days of culture in a microfluidic device again with no difference in absorbance observed between the preculture and following microfluidic culture conditions [32]. …”

“…Moreover, it could not be excluded that at higher mass inflow the sample would not touch the chamber walls due to flow pressure, so this positioning of the tissue would form a turbulent flow pattern with vorticities and zones with velocities close to zero. Device modeling has been utilized previously to develop designs that allow manipulation of different experimental conditions; for example, mathematical modeling described fluid dynamics alongside intracellular signaling as a key predictor in glucose uptake in adipose tissue [32] and assessment of oxygen delivery to tumor samples within a microfluidic device [31]. …”

3D-templated, fully automated microfluidic input/output multiplexer for endocrine tissue culture and secretion sampling

“…Our group 9–11 and others 12–21 have shown the utility of microsystems to study biological function of pancreatic islets, and we have begun applying these systems to studying primary adipose tissue function 11, 22 . Although some studies have leveraged microfluidics to assay secretion from adipocyte cell lines 23–25 , less has been accomplished toward studying dynamics of intact, primary adipose tissue on-chip 26 . In terms of fluid handling, although passively controlled microdevices provide simplicity of use 10, 11, 22, 27 , the precision in fluidic control provided by actively valved devices is virtually unmatched in gleaning complex functions from biological systems 28–31 .…”

Magnetic nanochain enabled microarray and microfluidic bioassays

“…This chip contains a high density of flow channels and pneumatic valves. 117 Microfluidic assay chips have been designed for major human disease such as cancer 118,119 , cardiovascular diseases 120,121 , infectious diseases 30,122 and metabolic syndrome 123 . Notably, two common structural components are often found in these chips: liquid mixer and biofunctionalized surface, although in different formats.…”