Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system

Oleaga, Carlota; Riu, Anne; Rothemund, Sandra; Lavado, Andrea; McAleer, Christopher W.; Long, Christopher J.; Persaud, Keisha; Narasimhan, Narasimhan Sriram; Tran, My N.; Roles, Jeffry; Carmona‐Moran, Carlos A.; Sasserath, Trevor; Elbrecht, Daniel; Kumanchik, Lee; Bridges, Lee; Martin, Candace; Schnepper, Mark T.; Ekman, Gail; Jackson, Max; Wang, Ying I.; Note, Reine; Langer, Jessica; Teissier, Silvia; Hickman, James J.

doi:10.1016/j.biomaterials.2018.07.062

Cited by 131 publications

(143 citation statements)

References 88 publications

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“…Such small molecule and multi-omic profiling can be accomplished using small sample volumes (<60 µL) [37,84,[89][90][91]. This allows for non-endpoint characterization of basal, diseased, drug-treated, or toxicant-challenged conditions over time as has been successfully conducted by multiple research groups using integrated multi-organ-on-a-chip models [83,92,93].…”

Section: Metabolic Functionality and Response Assessmentmentioning

confidence: 99%

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

et al. 2020

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Organs-on-a-Chip (OOAC) is a disruptive technology with widely recognized potential to change the efficiency, effectiveness, and costs of the drug discovery process; to advance insights into human biology; to enable clinical research where human trials are not feasible. However, further development is needed for the successful adoption and acceptance of this technology. Areas for improvement include technological maturity, more robust validation of translational and predictive in vivo-like biology, and requirements of tighter quality standards for commercial viability. In this review, we reported on the consensus around existing challenges and necessary performance benchmarks that are required toward the broader adoption of OOACs in the next five years, and we defined a potential roadmap for future translational development of OOAC technology. We provided a clear snapshot of the current developmental stage of OOAC commercialization, including existing platforms, ancillary technologies, and tools required for the use of OOAC devices, and analyze their technology readiness levels. Using data gathered from OOAC developers and end-users, we identified prevalent challenges faced by the community, strategic trends and requirements driving OOAC technology development, and existing technological bottlenecks that could be outsourced or leveraged by active collaborations with academia.

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Section: Metabolic Functionality and Response Assessmentmentioning

confidence: 99%

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

et al. 2020

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“…have been reported till date. [ 72–76 ] In addition, these platforms have been used to investigate the migration of cancer cells in a multi‐organ cell environment. [ 77 ] BOC systems have shown great potential in studying organ physiology, tissue development, and disease etiology.…”

Section: Organ‐on‐a‐chipmentioning

confidence: 99%

Emerging Trends in Microfluidics Based Devices

Solanki

Pandey

Gupta

et al. 2020

Biotechnology Journal

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One of the major challenges for scientists and engineers today is to develop technologies for the improvement of human health in both developed and developing countries. However, the need for cost-effective, high-performance diagnostic techniques is very crucial for providing accessible, affordable, and high-quality healthcare devices. In this context, microfluidic-based devices (MFDs) offer powerful platforms for automation and integration of complex tasks onto a single chip. The distinct advantage of MFDs lies in precise control of the sample quantities and flow rate of samples and reagents that enable quantification and detection of analytes with high resolution and sensitivity. With these excellent properties, microfluidics (MFs) have been used for various applications in healthcare, along with other biological and medical areas. This review focuses on the emerging demands of MFs in different fields such as biomedical diagnostics, environmental analysis, food and agriculture research, etc., in the last three or so years. It also aims to reveal new opportunities in these areas and future prospects of commercial MFDs.

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“…130,134,135 Liver metabolism that converts parent drugs into metabolites also accounts for a potential source of cardiotoxic effects that can only be predicted in vitro with interconnected heart-liver cellular systems. [136][137][138] Commonly screened cardiotoxicity mechanisms relate to electrophysiology, calcium cycling, mitochondrial function/bioenergetics, structural tissue and subcellular properties, contractility, and cell death. [129][130][131][132][133] In addition to assaying phenotypes and markers screening toxicity mechanisms, lists of compounds with known mechanistic drug effects are often used to validate drug development tools and serve as comprehensive controls.…”

Section: Toxicitymentioning

confidence: 99%

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Dame

Ribeiro

2020

Exp Biol Med (Maywood)

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Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects. Impact statement Cardiac and hepatic adverse drug effects are among the leading causes of attrition in preclinical and clinical drug development programs as well as marketing withdrawals. The insufficiency of animal testing models has led to considerable interest in the employment of cardiac and hepatic models using human-induced pluripotent stem cells (iPSCs) for drug toxicity testing. However, current batches of iPSC-derived cardiomyocytes and hepatocytes are variable and not matured as adult primary tissues, which limit their prediction of drug effects. This article discusses how the use of microfluidics can create microenvironments to better control differentiation protocols and increase the physiological relevance of iPSC-derived cardiomyocytes and hepatocytes. Development and standardization of technologies will enable evaluation of the potential value of cellular microsystems to improve the in vitro models used in drug development programs. Future steps in this field include controlled connections of organ systems to better recreate clinical metabolism and pharmacokinetics.

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Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system

Cited by 131 publications

References 88 publications

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

Emerging Trends in Microfluidics Based Devices

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

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