Prediction of hepatotoxicity for drugs using human pluripotent stem cell-derived hepatocytes.

Drug-induced liver toxicity is a main reason for withdrawals of new drugs in late clinical phases and post-launch of the drugs. Thus, hepatotoxicity screening of drug candidates in pre-clinical stage is important for reducing drug attrition rates during the clinical development process. Here, we show commercially available hepatocytes that could be used for early toxicity evaluation of drug candidates. From our hepatic differentiation technology, we obtained highly pure (≥98%) hepatocytes from human embryonic stem cells (hESCs) having mature phenotypes and similar gene expression profiles with those of primary human tissues. Furthermore, we optimized 96-well culture condition of hESC-derived hepatocytes suitable for toxicity tests in vitro. To this end, we demonstrated the efficacy of our optimized hepatocyte model for predicting hepatotoxicity against the Chinese herbal medicines and showed that toxicity patterns from our hepatocyte model was similar to those of human primary cultured hepatocytes. We conclude that toxicity test using our hepatocyte model could be a good alternative cell source for pre-clinical study to predict potential hepatotoxicity in drug discovery industries.

Investigation of an Optimal Material Addition Rate for Energy Consumption and Dimensional Accuracy in Fused Filament Fabrication of CFR-PEEK.

The material addition rate (MAR) of fused filament fabrication (FFF) is an indicator of process efficiency varied by process parameter settings, which affects energy consumption and part quality in FFF. This study aims to identify the optimal MAR of FFF using carbon-fiber-reinforced polyether-ether-ketone (CFR-PEEK) by considering a trade-off between energy consumption and the dimensional accuracy of FFF outputs. A design of experiments considering two main process parameters is planned to print three sample types through FFF for CFR-PEEK. Then, the MAR (i.e., deposited material volume per build time) of FFF is obtained to derive individual regression models of energy consumption and the dimensional accuracy measured for each sample type. Furthermore, a trade-off between energy consumption and dimensional accuracy on the MAR is formulated to derive an optimal MAR for each sample type. The results show that FFF for CFR-PEEK has a trade-off between energy consumption and dimensional accuracy; there exists a specific MAR that maximizes the overall performance of energy consumption and dimensional accuracy for each sample type. The optimal MAR is the highest for the small volume sample, whereas it becomes the lowest for the vertical build orientation sample. This study suggests that the optimal MAR should be flexibly adjusted based on a fabricated part. The findings from this study also address the fact that decision-making for optimal FFF operations needs a transition from the identification of specific process parameter settings to the management of a proper process efficiency level in FFF.

Simulating energy consumption based on material addition rates for material extrusion of CFR-PEEK: a trade-off between energy costs and cycle time.

While many studies for material extrusion-based additive manufacturing (AM) of polymers focus on experimental approaches to evaluate relevant performance measures from process parameters, there is a lack of discussion to connect experimental results with useful applications. Also, one of the major deficiencies in the application literature is a trade-off analysis between energy costs and cycle time (time to produce an item from the beginning to the end) since improving these two measures simultaneously is challenging. Thus, this paper proposes an energy simulation method for performing a trade-off analysis between energy costs and cycle time using combinations of major AM process parameters for material extrusion. We conduct experiments using carbon fiber-reinforced poly-ether-ether-ketone (CFR-PEEK), which is increasingly used in material extrusion. From experimental results, we build a power model in which power (kW) is derived as a linear function of material addition rates (MAR). This MAR regression model is then used in a proposed simulation model that integrates discrete event simulation and numerical simulation. In our simulation case study of 50 machines and 40 scenarios, we investigate trade-offs between energy costs and cycle time with three control policies (P1, P25, and P50) that allow 1, 25, or 50 machines to start heating, respectively. The trade-off analysis results show that P25 can be preferred when a balance between cycle time and energy costs is pursued, while P1 or P50 can be chosen if either energy cost (with P1) or cycle time (with P50) is more important than the other measure. Moreover, we find that the machine utilization, variability, and product volume have significant effects on energy costs and cycle time.

Human induced pluripotent stem cell line with cytochrome P450 enzyme polymorphism (CYP2C19*2/CYP3A5*3C) generated from lymphoblastoid cells.

Cytochrome P450 (CYP) comprises a superfamily of monooxygenase responsible for the metabolism of xenobiotics and approximately 75% of drugs in use today. Thus, genetic polymorphisms in CYP genes contribute to interindividual differences in hepatic metabolism of drugs, affecting on individual drug efficacy and may cause adverse effects. Here, we generated a human induced pluripotent stem cell (hiPSC) line with pharmacologically important traits (CYP2C19*2/CYP3A5*3C), which are highly polymorphic in Asian from lymphoblastoid cells. This hiPSC line could be a valuable source for predicting individual drug responses in the drug screening process that uses hiPSC-derived somatic cells, including hepatocytes.

Bio-inspired catechol chemistry: a new way to develop a re-moldable and injectable coacervate hydrogel.

A new way is demonstrated to develop a bio-inspired coacervate hydrogel by following catechol chemistry showing injectable and re-moldable physical properties. The formed coacervate shows potential long-term stability under water. Depending on pH, formation of the coacervate has been verified which is confirmed by XPS and zeta potential measurements.