Application of Organ-on-Chip in Drug Discovery

Nowadays the pharmaceutical industry is facing long and expensive drug discovery processes. Current preclinical drug evaluation strategies that utilize oversimplified cell cultures and animal models cannot satisfy the growing demand for new and effective drugs. The microengineered biomimetic system, namely organ-on-chip (OOC), simulating both the biology and physiology of human organs, has shown greater advantages than traditional models in drug efficacy and safety evaluation. The microengineered co-culture models recapitulate the complex interactions between different types of cells in vivo. Organ-on-chip system has also avoided the substantial interspecies differences in key disease pathways and disease-induced changes in gene expression profiles between human and other animal models. Biomimetic microsystems representing different organs have been integrated into a single microdevice and linked by a microfluidic circulatory system in a physiologically relevant manner. In this review, I outline the current development of organ-on-chip, and their applications in drug discovery. This human-on-chip system can model the complex, dynamic process of drug absorption, distribution, metabolism and excretion, and more reliably evaluate drug efficacy and toxicity. I also discuss, for the next generation of organ-on-chip, more research is required to identify suitable materials that can be used to mass produce organs-on-chips at low cost, and to scale up the system to be suitable for high-throughput analysis and commercial applications. There are more aspects that need to be further studied, thereby bring a much better tool to patients, drug developers, and clinicians.

Bridging the Gap:Integration of Artificial Intelligence with Organ-on-Chip(AI-OoC)

.Organ-on-Chip(OoC)has emerged as a revolutionary approach to emulate human organ function-ality in vitro,offering unparalleled insights into physiological processes and disease modeling.The integration of artificial intelligence(AI)with OoC platforms presents a transformative synergy,combining the precision of microscale organ replication with the analytical prowess of intelligent algorithms,is emerging as a transforma-tive force in harnessing the full potential of OoC.This perspective investigates the multifaceted implications of integrating AI with OoC,examining its impact on biomedical research,acknowledging the synergistic po-tential that arises from combining the precision of microscale organ replication with the analytical capabilities of intelligent algorithms,and fostering a future where the intricate workings of the technology and biology.

Ionic liquid-based transparent membrane-coupled human lung epithelium-on-a-chip demonstrating PM0.5 pollution effect under breathing mechanostress

The plausibility of human exposure to particulate matter(PM)has witnessed an increase within the last several years.PM of different sizes has been discovered in the atmosphere given the role of dust transport in weather and climate composition.As a regulator,the lung epithelium orchestrates the innate response to local damage.Herein,we developed a lung epithelium-ona-chip platform consisting of easily moldable polydimethylsiloxane layers along with a thin,flexible,and transparent ionic liquid-based poly(hydroxyethyl)methacrylate gel membrane.The epithelium was formed through the culture of human lung epithelial cells(Calu-3)on this membrane.The mechanical stress at the air–liquid interface during inhalation/exhalation was recapitulated using an Arduino-based servo motor system,which applied a uniaxial tensile strength from the two sides of the chip with 10%strain and a frequency of 0.2 Hz.Subsequently,the administration of silica nanoparticles(PM0.5)with an average size of 463 nm to the on-chip platform under static,dynamic,and dynamic+mechanical stress(DMS)conditions demonstrated the effect of environmental pollutants on lung epithelium.The viability and release of lactate dehydrogenase were determined along with proinflammatory response through the quantification of tumor necrosis factor-α,which indicated alterations in the epithelium.

Three-dimensional perfused human in vitro model of nonalcoholic fatty liver disease

AIM To develop a human in vitro model of non-alcoholic fatty liver disease(NAFLD), utilising primary hepatocytes cultured in a three-dimensional(3D) perfused platform. METHODS Fat and lean culture media were developed to directly investigate the effects of fat loading on primary hepatocytes cultured in a 3D perfused culture system. Oil Red O staining was used to measure fat loading in the hepatocytes and the consumption of free fatty acids(FFA) from culture medium was monitored. Hepatic functions, gene expression profiles and adipokine release were compared for cells cultured in fat and lean conditions. To determine if fat loading in the system could be modulated hepatocytes were treated with known anti-steatotic compounds. RESULTS Hepatocytes cultured in fat medium were found to accumulate three times more fat than lean cells and fat uptake was continuous over a 14-d culture. Fat loading of hepatocytes did not cause any hepatotoxicity and significantly increased albumin production. Numerous adipokines were expressed by fatty cells and genes associated with NAFLD and liver disease were upregulated including: Insulin-like growth factorbinding protein 1, fatty acid-binding protein 3 and CYP7A1. The metabolic activity of hepatocytes cultured in fatty conditions was found to be impaired and the activities of CYP3A4 and CYP2C9 were significantlyreduced, similar to observations made in NAFLD patients. The utility of the model for drug screening was demonstrated by measuring the effects of known antisteatotic compounds. Hepatocytes, cultured under fatty conditions and treated with metformin, had a reduced cellular fat content compared to untreated controls and consumed less FFA from cell culture medium.CONCLUSION The 3D in vitro NAFLD model recapitulates many features of clinical NAFLD and is an ideal tool for analysing the efficacy of anti-steatotic compounds.

Vascular units as advanced living materials for bottom-up engineering of perfusable 3D microvascular networks

The timely establishment of functional neo-vasculature is pivotal for successful tissue development and regen-eration,remaining a central challenge in tissue engineering.In this study,we present a novel(micro)vascular-ization strategy that explores the use of specialized“vascular units”(VUs)as building blocks to initiate blood vessel formation and create perfusable,stroma-embedded 3D microvascular networks from the bottom-up.We demonstrate that VUs composed of endothelial progenitor cells and organ-specific fibroblasts exhibit high angiogenic potential when embedded in fibrin hydrogels.This leads to the formation of VUs-derived capillaries,which fuse with adjacent capillaries to form stable microvascular beds within a supportive,extracellular matrix-rich fibroblastic microenvironment.Using a custom-designed biomimetic fibrin-based vessel-on-chip(VoC),we show that VUs-derived capillaries can inosculate with endothelialized microfluidic channels in the VoC and become perfused.Moreover,VUs can establish capillary bridges between channels,extending the microvascular network throughout the entire device.When VUs and intestinal organoids(IOs)are combined within the VoC,the VUs-derived capillaries and the intestinal fibroblasts progressively reach and envelop the IOs.This promotes the formation of a supportive vascularized stroma around multiple IOs in a single device.These findings un-derscore the remarkable potential of VUs as building blocks for engineering microvascular networks,with ver-satile applications spanning from regenerative medicine to advanced in vitro models.

Engineering human spinal microphysiological systems to model opioid-induced tolerance

pioids are commonly used for treating chronic pain.However,with continued use,they may induce tolerance and/or hyperalgesia,which limits therapeutic efficacy.The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied,in part,because current models cannot fully recapitulate human pathology.Here,we engineered novel human spinal microphysiological systems(MPSs)integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance.Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement.We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids,but also promotes their neuron maturation,neural activity,and functional development.We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia,as measured by altered neural activity,and downregulation ofμ-opioid receptor expression of human spinal MPSs.The MPSs are scalable,cost-effective,easy-to-use,and compatible with commonly-used well-plates,thus allowing plug-and-play measurements of neural activity.We believe the MPSs hold a promising translational potential for studying human pain etiology,screening new treatments,and validating novel therapeutics for human pain medicine.