A liver-on-a-chip platform with bioprinted hepatic spheroids

Bhise, Nupura S.; Manoharan, Vijayan; Massa, Solange; Tamayol, Ali; Ghaderi, Masoumeh; Miscuglio, Mario; Lang, Qi; Zhang, Yu Shrike; Shin, Su Ryon; Calzone, Giovanni; Annabi, Nasim; Shupe, Thomas; Bishop, Colin E.; Atala, Anthony; Dokmeci, Mehmet R.; Khademhosseini, Ali

doi:10.1088/1758-5090/8/1/014101

Cited by 480 publications

(466 citation statements)

References 75 publications

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“…A resealable microbioreactor for perfusion culture of organoids was developed by modifying our recently published protocols (48,54,55). The microbioreactor was designed to possess two hemichambers embedded within a pair of PDMS (top) and PDMS/glass (bottom) pieces, which were then sandwiched between two rigid supports made of PMMA and a thin PDMS cushion layer to ensure hydraulic tightness (Fig.…”

Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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595

571

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Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner. We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.organ-on-a-chip | microbioreactor | electrochemical biosensor | physical sensor | drug screening D rug discovery is a lengthy process associated with tremendous cost and high failure rate (1). On average, less than 1 in 10 drug candidates are eventually approved by the Food and Drug Administration (2), during which successful transition ratios to next phases are roughly 65, 32, and 60% for phase I, phase II, and phase III, respectively (3). Among the primary causes of failure, nonclinical/ clinical safety (>50%) and efficacy (>10%) stand out in the front, more than all other factors (e.g., strategic, commercial, operational) combined (3, 4). These two major causes not only contribute to the low success rates during the drug development but also lead to the withdrawal of approved drugs from the market. Among all of the drug attritions, it is estimated that safety liabilities related to the cardiovascular system account for 45%, whereas 32% are due to hepatotoxicity (5, 6). These high failure/attrition ratios of drugs SignificanceMonitoring human organ-on-a-chip systems presents a significant challenge, where the capability of in situ continual monitoring of organ behaviors and their responses to pharmaceutical compounds over extended periods of time is critical in understanding the dynamics of drug effects and therefore accurate prediction of human organ reacti...

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Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

595

571

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“…To conduct hepatotoxicity assessment studies, we used acetaminophen (APAP) as a model drug and evaluate the response of the platform against this drug. It is well known that exposure of hepatocytes to APAP can alter protein secretion rates which will be mediated by metabolic activities 40. In this study, 5 × 10 −3 and 10 × 10 −3 m APAP concentrations were utilized to induce hepatotoxicity as per the optimized dose reported in our previous study and other published literature.…”

Section: Resultsmentioning

confidence: 99%

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

et al. 2017

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Development of an efficient sensing platform capable of continual monitoring of biomarkers is needed to assess the functionality of the in vitro organoids and to evaluate their biological responses toward pharmaceutical compounds or chemical species over extended periods of time. Here, a novel label‐free microfluidic electrochemical (EC) biosensor with a unique built‐in on‐chip regeneration capability for continual measurement of cell‐secreted soluble biomarkers from an organoid culture in a fully automated manner without attenuating the sensor sensitivity is reported. The microfluidic EC biosensors are integrated with a human liver‐on‐a‐chip platform for continual monitoring of the metabolic activity of the organoids by measuring the levels of secreted biomarkers for up to 7 d, where the metabolic activity of the organoids is altered by a systemically applied drug. The variations in the biomarker levels are successfully measured by the microfluidic regenerative EC biosensors and agree well with cellular viability and enzyme‐linked immunosorbent assay analyses, validating the accuracy of the unique sensing platform. It is believed that this versatile and robust microfluidic EC biosensor that is capable of automated and continual detection of soluble biomarkers will find widespread use for long‐term monitoring of human organoids during drug toxicity studies or efficacy assessments of in vitro platforms.

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“…Bhise et al [93] constructed a liver-ona-chip platform of 3D printed hepatic spheroids for drug toxicity assessment, which could maintain its function after 30 days of culture. Matsusaki et al [94] constructed hierarchical liver tissue micro-arrays using HepG2/HUVECsladen fibronectin and gelatin.…”

Section: Bioprinting Of Livermentioning

confidence: 99%

3D bioprinting for cell culture and tissue fabrication

Jian

Wang

et al. 2018

Bio-des. Manuf.

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Three-dimensional (3D) bioprinting is a computer-assisted technology which precisely controls spatial position of biomaterials, growth factors and living cells, offering unprecedented possibility to bridge the gap between structurally mimic tissue constructs and functional tissues or organoids. We briefly focus on diverse bioinks used in the recent progresses of biofabrication and 3D bioprinting of various tissue architectures including blood vessel, bone, cartilage, skin, heart, liver and nerve systems. This paper provides readers a guideline with the conjunction between bioinks and the targeted tissue or organ types in structuration and final functionalization of these tissue analogues. The challenges and perspectives in 3D bioprinting field are also illustrated.

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A liver-on-a-chip platform with bioprinted hepatic spheroids

Cited by 480 publications

References 75 publications

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

3D bioprinting for cell culture and tissue fabrication

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