Organs-on-chips at the frontiers of drug discovery

Esch, Eric W.; Bahinski, Anthony; Huh, Dongeun

doi:10.1038/nrd4539

Cited by 993 publications

(803 citation statements)

References 104 publications

Supporting

Mentioning

759

Contrasting

Unclassified

Order By: Relevance

“…in human patients are mainly attributed to the inefficient validation based on planar static cell cultures and preclinical animal models for establishing drug efficacy and safety (7). Therefore, there is an urgent need for the development of human-based 3D organ models that precisely recapitulate the important physiology and function of their counterparts in humans as viable platforms for drug screening (8)(9)(10).…”

Section: Significancementioning

confidence: 99%

“…These miniaturized human organ models have several advantages over conventional models, such as more accurate prediction of human responses and, in particular, multiorgan interactions when different organ modules are assembled in a single fluid circuit (7,31). Although a majority of focus in the field has been placed on the construction of biomimetic organ models (7,15,(31)(32)(33), it is increasingly recognized that incorporating biosensing would allow for in situ monitoring of the status of these miniaturized organs (9,34). Such a need originates from the fact that many drugs can trigger chronic cellular reactions, whereas others may induce delayed cell responses.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

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.

624

571

View full text Add to dashboard Cite

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...

show abstract

Section: Significancementioning

confidence: 99%

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.

624

571

View full text Add to dashboard Cite

show abstract

“…The organ-on-a-chip field has witnessed remarkable progress in the past few years 8 . The emergence of organ-on-a-chip technology provides a valuable new approach to finely mimic functional units of a specific organ using perfusable micron-sized microfluidic devices.…”

Section: Introductionmentioning

confidence: 99%

Organic transistor platform with integrated microfluidics for in-line multi-parametric in vitro cell monitoring

et al. 2017

View full text Add to dashboard Cite

Future drug discovery and toxicology testing could benefit significantly from more predictive and multi-parametric readouts from in vitro models. Despite the recent advances in the field of microfluidics, and more recently organ-on-a-chip technology, there is still a high demand for real-time monitoring systems that can be readily embedded with microfluidics. In addition, multi-parametric monitoring is essential to improve the predictive quality of the data used to inform clinical studies that follow. Here we present a microfluidic platform integrated with in-line electronic sensors based on the organic electrochemical transistor. Our goals are twofold, first to generate a platform to host cells in a more physiologically relevant environment (using physiologically relevant fluid shear stress (FSS)) and second to show efficient integration of multiple different methods for assessing cell morphology, differentiation, and integrity. These include optical imaging, impedance monitoring, metabolite sensing, and a wound-healing assay. We illustrate the versatility of this multi-parametric monitoring in giving us increased confidence to validate the improved differentiation of cells toward a physiological profile under FSS, thus yielding more accurate data when used to assess the effect of drugs or toxins. Overall, this platform will enable high-content screening for in vitro drug discovery and toxicology testing and bridges the existing gap in the integration of in-line sensors in microfluidic devices.

show abstract

“…Problems arising in context of vascular grafts are protein and platelet adhesion that can lead to infections and occlusion as well as insufficient endothelialzation (Qi et al, 2013). Beyond that, directed and selective cell adhesion is required to elucidate various biological events ( Figure 5) (Esch et al, 2015;Khalili and Ahmad, 2015). Hence, new strategies to gain selective cell adhesion, recruitment of progenitor cells and subsequent differentiation, are developed.…”

Section: Components Of Multifunctional Biomaterials Coatingsmentioning

confidence: 99%

Multifunctional biomaterial coatings: synthetic challenges and biological activity

Pagel

Beck‐Sickinger

2017

Biological Chemistry

View full text Add to dashboard Cite

A controlled interaction of materials with their surrounding biological environment is of great interest in many fields. Multifunctional coatings aim to provide simultaneous modulation of several biological signals. They can consist of various combinations of bioactive, and bioinert components as well as of reporter molecules to improve cell-material contacts, prevent infections or to analyze biochemical events on the surface. However, specific immobilization and particular assembly of various active molecules are challenging. Herein, an overview of multifunctional coatings for biomaterials is given, focusing on synthetic strategies and the biological benefits by displaying several motifs.

show abstract

Organs-on-chips at the frontiers of drug discovery

Cited by 993 publications

References 104 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

Organic transistor platform with integrated microfluidics for in-line multi-parametric in vitro cell monitoring

Multifunctional biomaterial coatings: synthetic challenges and biological activity

Contact Info

Product

Resources

About