A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications

Abstract

There is a growing awareness that complex 3-dimensional (3D) organs are not well represented by monolayers of a single cell type - the standard format for many drug screens. To address this deficiency, and with the goal of improving screens so that drugs with good efficacy and low toxicity can be identified, microphysiological systems (MPS) are being developed that better capture the complexity of in vivo physiology. We have previously described an organ-on-a-chip platform that incorporates perfused microvessels, such that survival of the surrounding tissue is entirely dependent on delivery of nutrients through the vessels. Here we describe an arrayed version of the platform that incorporates multiple vascularized micro-organs (VMOs) on a 96-well plate. Each VMO is independently-addressable and flow through the micro-organ is driven by hydrostatic pressure. The platform is easy to use, requires no external pumps or valves, and is highly reproducible. As a proof-of-concept we have created arrayed vascularized micro tumors (VMTs) and used these in a blinded screen to assay a small library of compounds, including FDA-approved anti-cancer drugs, and successfully identified both anti-angiogenic and anti-tumor drugs. This 3D platform is suitable for efficacy/toxicity screening against multiple tissues in a more physiological environment than previously possible.

Advances in predictive in vitro models of drug-induced nephrotoxicity

“…Advances in the past couple of years have led to the development of high-throughput platforms with vascularized microorgans in a 96-well format, with the intent of recreating tissues with multiple cell types for rapid screening of large drug libraries. So far, however, the microorgans studied with these platforms have been restricted to simple architectures, such as tumour models, and renal models have not yet been produced with this design 140,141 .…”

3D bioprinting for cardiovascular regeneration and pharmacology

“…Vasculature in the circulatory system mainly involves coronary vasculature and microvasculature. Differing from the capillaries that rely on angiogenesis (native sprouting process) stimulated by existing vasculature, perfusable vasculature requires the formation of endothelialized lining over the lumen [76,201–204]. In our previous review paper, we discussed three approaches for, and outlined both the advantages and weakness of manufacturing interconnected vessels, including (i) indirect bioprinting through utilizing sacrificial templates (a fugitive ink) that is removed to create hollow channels in a bulk construct; (ii) directly bioprinting interconnected channels in a construct, and (iii), direct bioprinting of a vasculature network or blood vessel in a tubular shape [16].…”

Tissue chips – innovative tools for drug development and disease modeling

“…For example, vincristine caused disruption in the microvasculature and resulting decreases in microtumor size, whereas oxaliplatin acted on cancer cells but left the vasculature intact. This platform has now been adapted to 96-well arrays for higher-throughput screening and toxicity testing of angiogenic and chemotherapeutic agents 65 .…”