Researchers from NIH, the Food and Drug Administration and the Defense Advanced Research Projects Agency collaborate to improve the process for predicting whether new drugs will be safe or toxic in people. Current ways of predicting toxicity include testing a potential drug in animals, such as mice and rats. This procedure is expensive and often unreliable in that it doesn’t always predict what happens in people.
Through the Tissue Chip for Drug Screening program at NCATS, researchers are developing 3-D human tissue chips. These human microphysiological systems — “organs on a chip” — are miniature platforms intended to model accurately the structure and function of the 10 human organ systems, such as the respiratory system, circulatory system and nervous system. Once these miniaturized models are developed, researchers can use them to test a potential drug, vaccine or biologic agent for toxic effects. Because these chips will be working models of human systems, investigators can use them to determine whether a substance is likely to be safe or toxic in people in a faster, more cost-effective manner than current methods.
On Dec. 20, 2013, the journal Stem Cell Research & Therapy published a supplement that provides an overview of the Tissue Chip projects. Stem Cells on Bioengineered Microphysiological Platforms for Disease Modeling and Drug Testing features reviews of the progress NCATS grantees have made to date on innovative cell resources and model systems. Following a brief introduction authored in part by NCATS’ Danilo Tagle, Ph.D., who oversees the Tissue Chip program, 18 projects are highlighted.
Introduction
Currently, only 18 percent of new therapeutic compounds ever reach phase II human trials. Of those that pass that test, only half are successful in phase III trials, which means enormous effort and resources are spent on drug candidates that ultimately fail. One of the most common reasons for these late failures is unanticipated toxicity based on previous preclinical data. Use of organ systems on a chip developed through this initiative could provide better models for testing new drugs and vaccines and predicting their safety and efficacy in clinical trials. These models could lower the number of toxic agents that appear in late-stage clinical testing, reduce the need to withdraw newly approved therapies from the market and minimize adverse events due to unidentified drug toxicities.
Reviews
Building Additional Complexity to In Vitro-Derived Intestinal Tissues
These researchers discuss ways to make in vitro systems that are complex enough to model common intestinal illnesses comprehensively. For example, current models lack the nerves necessary for the typical gut contraction and relaxation that pushes food through the digestive tract. More biologically complete models of the human intestine could enable previously impossible cellular and molecular studies of normal and abnormal gut function. Such models also could provide a platform on which to look at the absorption and effectiveness of new drugs prior to clinical studies. And, principles learned in this study may be applicable to how nerves are formed and integrated in other in vitro organ systems.
Building a Microphysiological Skin Model from Induced Pluripotent Stem Cells
Model systems are needed that reliably represent both intact tissue and the interaction of a particular tissue with other systems in the body. Many drugs are designed for topical application to the skin, making it the first organ exposed. In addition, skin is often the first organ to show a reaction after system-wide drug delivery. The researchers discuss their strategy to use a type of adult human stem cell to develop an organ on a chip system that resembles and functions like human skin and can be used for analyzing drug interactions with the skin.
Human Enteroids: Preclinical Models of Non-Inflammatory Diarrhea
Researchers need a model of the human intestine that is both readily available and easy to use. Such a model could help scientists better understand the way the human intestine works and the functional changes in the intestine associated with diseases. This kind of model also would be a good platform for testing new drug therapies. The researchers describe their project to establish cultures of cellular structures that functionally represent each major section of the intestine. These structures, called enteroids, can be used as a preclinical model to study the functional changes associated with non-inflammatory (small intestinal) and inflammatory diarrheas and to develop drug therapies.
Toward a 3-D Model of Human Brain Development for Studying Gene/Environment Interactions
Project investigators aim to establish and characterize an in vitro model of the developing human brain so that they can test drugs and environmental agents. To be accurate, they need a model that is complex enough to show the interactions between different types of brain cells, such as glial cells and neurons. The model in this project is designed to assess the neurotoxic effects of various chemical agents on the unique processes that occur during human brain development. The researchers will use adult human stem cells derived from people with diverse genetic backgrounds, including those with neurodevelopmental disorders. Such a model will be a useful tool for research into central nervous system function and changes in function associated with diseases.
These investigators are developing human cell-based tissue culture models of chronic conditions of the digestive tract, such as Crohn’s disease. These conditions share inflammation as a key driver in their development. With these model systems, the investigators plan to explore the effects of the body’s response to inflammation. These novel model systems could help scientists better understand chronic inflammatory disorders and foster the development of novel therapies and preventive strategies for digestive tract conditions.
Three-Dimensional Osteochondral Microtissue to Model Pathogenesis of Osteoarthritis
To develop drugs for osteoarthritis, researchers must first understand what causes the disease and how it develops. Project investigators are constructing an in vitro 3-D microsystem that models the structure and biology of the bone-cartilage complexes found at joints like the knee. They hope this will be the first step toward an improved in vitro model that can be used to predict the efficacy, safety and toxicology of candidate drugs to treat osteoarthritis.
Novel In Vitro Respiratory Models to Study Lung Development, Physiology, Pathology and Toxicology
Development of in vitro human lung tissue models would help bridge the current gap in knowledge of lung development, function and the changes lungs undergo due to disease or injury. Current in vitro lung models enable researchers to test hypotheses generated from human or animal studies directly in engineered human tissue models. These results already have been used to examine cell-based responses, physiological functions, unhealthy changes and even drug toxicity or responses. These investigators plan to create models with specific genetic profiles so they can test the importance of single gene products or pathways. In the future, model design will allow for linking of lung-on-a-chip devices to other organ systems, such as the heart, offering a more complete study of human drug responses.
This project team is developing an integrated platform with functionally connected blood vessel, liver and heart microtissues derived from a single line of adult human stem cells. This integrated system enables measurement of human physiological function, in real time, with readouts of all three systems. It also will be compatible with high-throughput analysis of responses to new drug therapy candidates, potentially transforming preclinical drug screening. In this paper, the investigators summarize their progress during the first year of the project.
Microphysiological Systems and Low-Cost Microfluidic Platform with Analytics
A functional multi-organ, human in vitro assay system would give researchers a more biologically accurate model for studying human disease and encourage basic and applied research. The system also would be of tremendous benefit in drug discovery and toxicology studies. This team describes its progress in developing a “body-on-a-chip” and the critical difficulties ahead as they continue development of these systems.
This research team has developed a 3-D model of the human skeletal muscle system that is connected to a vascular system consisting of a tissue-engineered blood vessel as part of a high-pressure arterial system. The muscle tissue reproduces the key functions of skeletal muscle in a living organism. This versatile system can be integrated with other organ systems and allows for noninvasive monitoring and assessment of tissue health response to drugs and poisons.
All-Human Microphysical Model of Metastasis Therapy
The investigators on this project are developing a human model of metastatic seeding (the spread of cancer cells throughout the body from the original tumor) that demonstrates metastatic growth. Scientists can probe this tiny bioreactor in real time to view a critical window into the abnormal physiology of metastasis and the pharmacology of metastatic tumor drug resistance. The model incorporates human breast cancer cells and liver cells — the liver is a major site of metastasis for a variety of cancers. This model of metastasis could provide information about how cancer cells spread and how they react to cancer drugs, enabling better clinical monitoring and improving clinical study design so that the effectiveness and safety of cancer treatments may be better understood.
A Human Pluripotent Stem Cell Platform for Assessing Developmental Neural Toxicity Screening
Researchers know surprisingly little about the hazards to human health posed by many of the tens of thousands of chemicals now in use. A primary reason for this knowledge gap is the lack of an affordable and effective way to test and screen chemicals. Project investigators review current methods of screening chemicals for toxicity in the nervous system and analyze these methods’ limitations. The project investigators are building a platform using adult human stem cells that scientists can use to test for developmental neural toxicity.
In this review, researchers describe development of a functional model of the female reproductive tract. This system produces hormones for reproductive function and cardiovascular, bone and sexual health, and it supports fetal development. The research team’s model uses a biological supporting structure to house the reproductive cells and a micro-scale circulatory system to support cell differentiation into multiple types, including epithelia, germ and somatic cells. This variety of female reproductive cells will all be developed from adult human stem cells.
The project investigators provide a summary of the different approaches used to engineer in vitro constructs of human heart muscle and liver tissue, derived from adult human stem cells. The goal is to produce fully functional, 3-D heart and liver models on a chip. The investigators propose that these in vitro platforms can be used successfully for high-throughput screening for drug safety and effectiveness, reducing the need for often unreliable animal studies.
Posted February 2014
