A robotic platform for fluidically-linked human body-on-chips experimentation

Abstract

Here we describe of an 'Interrogator' instrument that uses liquid-handling robotics, a custom software package, and an integrated mobile microscope to enable automated culture, perfusion, medium addition, fluidic linking, sample collection, and in situ microscopic imaging of up to 10 Organ Chips inside a standard tissue culture incubator. The automated Interrogator platform maintained the viability and organ-specific functions of 8 different vascularized, 2-channel, Organ Chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier (BBB), and brain) for 3 weeks in culture when fluidically coupled through their endothelium-lined vascular channels using a common blood substitute medium. When an inulin tracer was perfused through the multi-organ Human Body-on-Chips (HuBoC) fluidic network, quantitative distributions of this tracer could be accurately predicted using a physiologically-based multi-compartmental reduced order (MCRO) in silico model of the experimental system derived from first principles. This automated culture platform enables non-invasive imaging of cells within human Organ Chips and repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling, which should facilitate future HuBoc studies and pharmacokinetics (PK) analysis in vitro.Vascularized human Organ Chips are microfluidic cell culture devices containing separate vascular and parenchymal compartments lined by living human organ-specific cells that recapitulate the multicellular architecture, tissue-tissue interfaces, and relevant physical microenvironments of key functional units of living organs, while providing vascular perfusion in vitro 1,2 . The growing recognition that animal models do not effectively predict drug responses in humans 3-5 and the related increase in demand for in vitro human toxicity and efficacy testing, has led to pursuit of time-course analyses of human Organ Chip models and fluidically linked,

Combined Effects of Electric Stimulation and Microgrooves in Cardiac Tissue‐on‐a‐Chip for Drug Screening

“…[ 4 ] These systems have been developed for an array of organs, including the liver, [ 5 ] heart, [ 6 ] lung, [ 7 ] kidney, [ 8 ] and immune systems, [ 9 ] which could play crucial roles in the drug development process. [ 10,11 ]…”

Developmental bioengineering: recapitulating development for repair

“…Some of these systems are designed specifically as physiologically-based pharmacokinetic models for evaluating human drug responses, while others serve as niches for inducing growth of multiple progenitors, in order to build synthetic organs with highly differentiated compartments, such as kidneys. 56,75 Among these systems are (1) body-onchip organ systems, fluidically-linked to emulate integrated multi-organ function, [75][76][77][78] (2) body-on-chip organoid systems that consist of fluidically interconnected organoids, 79 and 3EcoFABs, specially-designed as microbial ecosystems coupled with standardized workflows, computational tools, and computational models. 80 Case study: repair of retina and spinal cord This section presents two case studies.…”

Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases

“…Recently, vascularized microfluidic LOCs have revolutionized the in vitro tissue and organ models, and resulted in the development of vascularized models of, retina [29], skin [30], hair [31], bone [32], thyroid [33], heart [34], lungs, [35], kidney [36], pancreas [37], liver [38], and intestine [39], respectively. A vascularized body-on-chip, linking eight different organs, including the brain and a BBB, transforming the future drug screening technology, was also reported [40]. The human-like perfusability, dynamic microenvironment, and the ability to carry out robust, rapid and reproducible assays in a controlled operational condition, with high throughput screening readouts, have made the above devices a super-tool to screen angiogenic drugs [41].…”

“…The human-like perfusability, dynamic microenvironment, and the ability to carry out robust, rapid and reproducible assays in a controlled operational condition, with high throughput screening readouts, have made the above devices a super-tool to screen angiogenic drugs [41]. Some of the above devices were already evaluated for drug screening [32,34,36,38,40], and a few studied the effect of NPs [35,41] and NMs [39].Microfluidic technology has also been used to model brain vasculogenesis/angiogenesis [42][43][44][45][46], BBB [2,42,[47][48][49][50][51][52][53], brain tissues [54,55], and brain angiogenesis-related cellular events such as inflammation [47,50], cell migration [56], cell-cell interactions [57], etc., see Table 2. In addition, specific conditions, involving pathological-angiogenesis, such as brain tumors [46,[54][55][56]58], ischemic strokes [59], and neurodegenerative disorders including Alzheimer's disease (AD) [60], Parkinson's disease (PD) [61], and Huntington's disease (HD) [62], could also be created on-chip.In addition to this, LOCs have been developed for studying the biocompatibility, cellular uptake and transport of NMs [2,27], many of them focusing on brain angiogenesis [2,45,…”

“…The human-like perfusability, dynamic microenvironment, and the ability to carry out robust, rapid and reproducible assays in a controlled operational condition, with high throughput screening readouts, have made the above devices a super-tool to screen angiogenic drugs [41]. Some of the above devices were already evaluated for drug screening [32,34,36,38,40], and a few studied the effect of NPs [35,41] and NMs [39].…”