Microphysiological heart–liver body-on-a-chip system with a skin mimic for evaluating topical drug delivery

Mello, Camilly P Pires de; Carmona‐Moran, Carlos A.; McAleer, Christopher W.; Perez, J.L. M.; Coln, Elizabeth A.; Long, Christopher J.; Oleaga, Carlota; Riu, Anne; Teissier, Silvia; Langer, Jessica; Hickman, James J.

doi:10.1039/c9lc00861f

Cited by 63 publications

(53 citation statements)

References 44 publications

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“…The importance of the utilization of serum-free culture helps to move away from animal models, and better predict human outcome with improved experimental consistency. In addition, using a defined medium composition and keeping a 2D configuration allows for integrating this hepatic model into several human multi-organ platforms to study the hepatic influence to neighbor organs under drug treatments, 49,[51][52][53] or in long-term exposures, 50,53 studies that were only possible before in in vivo models.…”

Section: Discussionmentioning

confidence: 99%

“…The technology developed can be easily transferred to other research laboratories and be integrated as part of multi-organ in vitro platforms to study the role of the hepatic function on other organ representatives. [49][50][51][52][53] 2 | MATERIAL AND METHODS…”

Section: Introductionmentioning

confidence: 99%

“…The straightforward engineering of the reported system can improve the quality of human based in vitro platforms by moving away from animal use and better predicting human outcomes. The technology developed can be easily transferred to other research laboratories and be integrated as part of multi‐organ in vitro platforms to study the role of the hepatic function on other organ representatives 49‐53 …”

Section: Introductionmentioning

confidence: 99%

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A functional long‐term 2D serum‐free human hepatic in vitro system for drug evaluation

Oleaga

Bridges

Persaud

et al. 2020

Biotechnology Progress

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Human in vitro hepatic models generate faster drug toxicity data with higher human predictability compared to animal models. However, for long-term studies, current models require the use of serum and 3D architecture, limiting their utility. Maintaining a functional long-term human in vitro hepatic culture that avoids complex structures and serum would improve the value of such systems for preclinical studies. This would also enable a more straightforward integration with current multi-organ devices to study human systemic toxicity to generate an alternative model to chronic animal evaluations. A human primary hepatocyte culture system was characterized for 28 days in 2D and serum-free defined conditions. Under the studied conditions, human primary hepatocytes maintained their characteristic morphology, hepatic markers and functions for 28 days. The acute and chronic administration of known drugs validated the sensitivity of the system for drug testing. This human 2D model represents a realistic system to evaluate hepatic function for longterm drug studies, without the need of animal serum, confounding variable in most models, and with less complexity and resultant cost compared to most 3D models. The defined culture conditions can easily be integrated into complex multi-organ in vitro models for studying systemic effects driven by the liver function for longterm evaluations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A functional long‐term 2D serum‐free human hepatic in vitro system for drug evaluation

Oleaga

Bridges

Persaud

et al. 2020

Biotechnology Progress

Self Cite

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“…Furthermore, they can also be used to assess a compound effectiveness [13,133]. De Melo et al developed a heart-liver-skin device for the systemic evaluation of drugs administrated topically and for the comparison of acute and systemic toxicity (Figure 2B) [67]. [125] under terms of the Creative Commons Attribution License.…”

Section: Body-on-a-chip or Human-on-a-chip For Adme Evaluation And Preclinical Developmentmentioning

confidence: 99%

Organ-on-a-Chip systems for new drugs development

2021

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Research on alternatives to the use of animal models and cell cultures has led to the creation of organ-on-a-chip systems, in which organs and their physiological reactions to the presence of external stimuli are simulated. These systems could even replace the use of human beings as subjects for the study of drugs in clinical phases and have an impact on personalized therapies. Organ-on-a-chip technology present higher potential than traditional cell cultures for an appropriate prediction of functional impairments, appearance of adverse effects, the pharmacokinetic and toxicological profile and the efficacy of a drug. This potential is given by the possibility of placing different cell lines in a three-dimensional-arranged polymer piece and simulating and controlling specific conditions. Thus, the normal functioning of an organ, tissue, barrier, or physiological phenomenon can be simulated, as well as the interrelation between different systems. Furthermore, this alternative allows the study of physiological and pathophysiological processes. Its design combines different disciplines such as materials engineering, cell cultures, microfluidics and physiology, among others. This work presents the main considerations of OoC systems, the materials, methods and cell lines used for their design, and the conditions required for their proper functioning. Examples of applications and main challenges for the development of more robust systems are shown. This non-systematic review is intended to be a reference framework that facilitates research focused on the development of new OoC systems, as well as their use as alternatives in pharmacological, pharmacokinetic and toxicological studies.

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“…Specifically, liver metabolism is a key modulator of drug toxicity in various other organs. Several recent studies have tackled the challenge of linking liver models to other organ and tissue models (Lee and Sung, 2018;Boeri et al, 2019;Baert et al, 2020;Pires de Mello et al, 2020). Since cardiotoxicity is the most common cause for safety-related market withdrawal, in this study we focused on heart-liver cross talk as one clinically relevant organ pair.…”

Section: Introductionmentioning

confidence: 99%

Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

et al. 2021

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Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both created with the same hiPSC line—to study drug–drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background.

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Microphysiological heart–liver body-on-a-chip system with a skin mimic for evaluating topical drug delivery

Abstract: Body-on-a-chip in vitro systems are a promising technology that aims to increase the predictive power of drug efficacy and toxicity in humans when compared to traditional animal models.

Cited by 63 publications

References 44 publications

A functional long‐term 2D serum‐free human hepatic in vitro system for drug evaluation

A functional long‐term 2D serum‐free human hepatic in vitro system for drug evaluation

Organ-on-a-Chip systems for new drugs development

Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

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