The pharmaceutical industry is facing a tremendous challenge in the drug development and testing pipeline; many questions and concerns have been raised about the efficiency effectiveness of current drug screening approaches. The cost of bringing a single drug to market is now estimated at a billion dollars and a major portion of this money is invested in preclinical stages where researchers test for the efficacy and safety of drugs. The current gold standards in such testing are a) animal testing b) simple in-vitro models of different organs where liver is considered the most important target both in terms of its drug metabolic functions and susceptibility to toxicity. Unfortunately, these current gold standards have low predictive capabilities which necessitated current research initiatives both in US and EU to replace those with microfluidic tissue models; these are expected to provide better physiological recapitulation and thereby better toxicological predictivity of new compounds. Our group among a few others are developing such models. Nevertheless, no current models take into account the zonation in the liver - in a controlled and actively enforced fashion - which can give rise to drastic differences in drug metabolic and detoxifying activity across the liver as wel zone specific toxicity. Accordingly in this application we aim to address this gap and build on our liver tissue engineering and microfabrication expertise towards developing a novel microfluidic platform that incorporates an actively controlled liver zonation. We will achieve this by integrating several key advances developed in our lab such as a multi-layer microfluidic culture device, actively controlled gradient generator and an ultra-thin collagen coating.
In aim 1, we wil first use this newly developed platform to characterize the zonation in a mono-culture of human hepatocytes and then demonstrate the zone-specific response of this platform by challenging it with drugs known to induce zone-specific toxicity.
In aim 2, we will expand this platform to include human liver sinusoidal endothelial cells and will then gauge the effect of interaction between hepatocytes and the endothelial cells on both cell types when the system is challenged in a similar fashion as in aim 1. The work, we describe here, is expected to establish the foundation of a realistic microfluidic liver co-culture model which controllably recapitulates zona response within a liver sinusoid. This is a significant advance that will not only enable better prediction of drug responses but will also provide high fidelity fundamental information about liver physiology. This will result in reduction of drug development costs as well as number of drugs that make it to the market with harmful effects; both results will greatly be beneficial to te general public.

Public Health Relevance

Owing to its central role in drug metabolism, the liver is also one of the main targets for the toxic effects of xenobiotics. Accordingly, accurate prediction of toxicity of a variety of compounds using in-vitro liver models is a significant step towards reducing animal use for such studies and accordingly reduction in drug development costs. In this project we will build a microfluidic liver model that aims to recapitulate the heterogeneity o liver cells (zonation) across a liver sinusoid; this will result in tremendously improved predictio of the effect of pharmaceutical compounds that have zone-specific toxic effects. We will achieve this by integrating several key advances developed in our lab such as a multi-layer microfluidic culture device, actively controlled gradient generator and an ultra-thin collagen coating.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB020192-02
Application #
9136839
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Selimovic, Seila
Project Start
2015-09-03
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Kang, Young Bok Abraham; Eo, Jinsu; Mert, Safak et al. (2018) Metabolic Patterning on a Chip: Towards in vitro Liver Zonation of Primary Rat and Human Hepatocytes. Sci Rep 8:8951
Huang, Haishui; Yarmush, Martin L; Usta, O Berk (2018) Long-term deep-supercooling of large-volume water and red cell suspensions via surface sealing with immiscible liquids. Nat Commun 9:3201
Gokduman, Kurtulus; Bestepe, Furkan; Li, Lei et al. (2018) Dose-, treatment- and time-dependent toxicity of superparamagnetic iron oxide nanoparticles on primary rat hepatocytes. Nanomedicine (Lond) 13:1267-1284
Gokaltun, Aslihan; Yarmush, Martin L; Asatekin, Ayse et al. (2017) Recent advances in nonbiofouling PDMS surface modification strategies applicable to microfluidic technology. Technology (Singap World Sci) 5:1-12
Huang, Haishui; Yu, Yin; Hu, Yong et al. (2017) Generation and manipulation of hydrogel microcapsules by droplet-based microfluidics for mammalian cell culture. Lab Chip 17:1913-1932
Serpooshan, Vahid; Chen, Pu; Wu, Haodi et al. (2017) Bioacoustic-enabled patterning of human iPSC-derived cardiomyocytes into 3D cardiac tissue. Biomaterials 131:47-57
McCarty, William J; Usta, O Berk; Yarmush, Martin L (2016) A Microfabricated Platform for Generating Physiologically-Relevant Hepatocyte Zonation. Sci Rep 6:26868
Prodanov, Ljupcho; Jindal, Rohit; Bale, Shyam Sundhar et al. (2016) Long-term maintenance of a microfluidic 3D human liver sinusoid. Biotechnol Bioeng 113:241-6
Bhushan, Abhinav; Martucci, Nicole J; Usta, O Berk et al. (2016) New technologies in drug metabolism and toxicity screening: organ-to-organ interaction. Expert Opin Drug Metab Toxicol 12:475-7
Bale, Shyam Sundhar; Sridharan, Gautham Vivek; Golberg, Inna et al. (2015) A novel low-volume two-chamber microfabricated platform for evaluating drug metabolism and toxicity. Technology (Singap World Sci) 3:155-162

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