Qualifying a human Liver-Chip for predictive toxicology: Performance assessment and economic implications

Abstract

Human organ-on-a-chip (Organ-Chip) technology has the potential to disrupt preclinical drug discovery and improve success in drug development pipelines as it can recapitulate organ-level pathophysiology and clinical responses. The Innovation and Quality (IQ) consortium, formed by multiple pharmaceutical and biotechnology companies, has published guidelines that define criteria for qualifying preclinical models, however, systematic and quantitative evaluation of the predictive value of Organ-Chips has not yet been reported. Here, 780 Liver-Chips were analyzed to determine their ability to predict drug-induced liver injury (DILI) caused by small molecules identified as benchmarks by the IQ consortium. The Liver-Chip met the qualification guidelines across a blinded set of 27 known hepatotoxic and non-toxic drugs with a sensitivity of 80% and a specificity of 100%. A computational economic value analysis suggests that with this performance the Liver-Chip could generate $3 billion annually for the pharmaceutical industry due to increased R&D productivity.

Phenotypic Characterization of Liver Sinusoidal Endothelial Cells on the Human Liver-Chip for Potential in vitro Therapeutic Antibody Pharmacology Applications

“…However, donors 2 and 4 demonstrated approximately a 20% decline in cell number by Day 14 as observed through bright-field imaging (scoring performed according to supplementary figure S2, donor 4 in supplementary figure S3). Similar LSEC morphology was demonstrated by donor one in a liver organoid model [23] and by donor three in human coculture [25], [30] and quad-culture [24] Liver-Chips, respectively.…”

“…However, donors 2 and 4 demonstrated approximately a 20% decline in cell number by Day 14 as observed through bright-field imaging (scoring performed according to supplementary figure S2, donor 4 in supplementary figure S3). Similar LSEC morphology was demonstrated by donor one in a liver organoid model [23] and by donor three in human coculture [25], [30] and quad-culture [24] Liver-Chips, respectively. SEM is the gold standard for visualizing the ultrastructure of cells and reveals that 2-20% of the LSEC surface is covered with fenestrae that are either individually scattered or arranged in a sieve-like pattern [32] with no basement membrane, and no cytoplasmic projections such as filopodia [33].…”

“…Donors 2 and 3 were evaluated in two independent experiments. The Liver-chip coating, seeding, and connection were conducted according to previously published protocols [24], [25]. Briefly, before cell seeding, Liver-Chips (S1 Chip®, Emulate Inc.) were surface-functionalized using reagents ER-1™ (Emulate reagent: 10461) and ER-2™ (Emulate reagent: 10462).…”

Microfluidic Organ-on-a-Chip Devices for Liver Disease Modeling In Vitro

“…One of the beneficial potentials and future perspectives of microfluidic devices was reported by Ewart et al, who analyzed Liver-Chip for its ability to predict DILI [ 106 ]. This study reported 80% sensitivity of compound toxicities, which has a significant potential in drug development, especially preclinical stage.…”

“…This study reported 80% sensitivity of compound toxicities, which has a significant potential in drug development, especially preclinical stage. Moreover, the economic value model in the pharmaceutical industry for increased precision of preclinical studies estimated approximately USD 3 billion in benefits for Liver-Chip studies and for the use of other organ-chips with the same sensitivity up to USD 24 billion in benefits [ 106 ].…”