Microfluidic devices lined with living human cells for drug development, disease modeling, and personalized medicine

Clinical studies take years to complete and testing a single compound can cost more than $2 billion. Meanwhile, innumerable animal lives are lost, and the process often fails to predict human responses because traditional animal models often do not accurately mimic human pathophysiology. For these reasons, there is a broad need for alternative ways to model human diseases in vitro in order to accelerate the development of new drugs and advance personalized medicine.

Wyss Institute researchers and a multidisciplinary team of collaborators have adapted computer microchip manufacturing methods to engineer microfluidic culture devices that recapitulate the microarchitecture and functions of living human organs, including the lung, intestine, kidney, skin, bone marrow and blood-brain barrier, among others. These microdevices, called ‘Organs-on-Chips’ (Organ Chips), offer a potential alternative to traditional animal testing. Each Organ Chip is composed of a clear flexible polymer about the size of a computer memory stick that contains hollow microfluidic channels lined by living human organ-specific cells interfaced with a human endothelial cell-lined artificial vasculature, and mechanical forces can be applied to mimic the physical microenvironment of living organs, including breathing motions in lung and peristalsis-like deformations in the intestine. They are essentially living, three-dimensional cross-sections of major functional units of whole living organs. Because they are translucent, they provide a window into the inner workings of human cells in living tissues within an organ-relevant context.

We took a game-changing advance in microengineering made in our academic lab, and in just a handful of years, turned it into a technology that is now poised to have a major impact on society. Donald Ingber

With their ability to host and combine the different cell and tissue types making up human organs, Organ Chips present an ideal microenvironment to study molecular- and cellular-scale activities that underlie human organ function and mimic human-specific disease states, as well as identify new therapeutic targets in vitro. They recreate therapeutically relevant interfaces, like the alveolar-capillary interface and blood-brain-barrier, to investigate drug delivery as well as discover new therapeutics. Organ Chips also can be used to culture a living microbiome for extended times in direct contact with living human intestinal cells to enable insights into how these microbes influence health and disease, or to model lung infections with influenza virus to identify its vulnerabilities. They also open up new possibilities to investigate how environmental factors like cigarette smoke affect tissue health and physiology in individual patients, as shown with a smoking machine that precisely mimics human smoking behavior and its impact on human lung airway functions by breathing cigarette smoke directly into the airspace of a human Lung Airway Chip.

Play This short video explains how the design of the chips allows them to emulate organ–level functions. Credit: Wyss Institute at Harvard University

To mimic the interconnectedness of organs within the human body, Wyss researchers also have developed an automated instrument to link multiple Organ Chips together by transferring fluid between their common vascular channels. This instrument, designed to mimic whole-body physiology, controls fluid flow and cell viability while permitting real-time observation of the cultured tissues and the ability to analyze complex interconnected biochemical and physiological responses across ten different organs. This holistic “human Body-on-Chips” approach is being used to predict human pharmacokinetic and pharmacodynamics (PK/PD) responses of drugs in vitro.

A Wyss Institute-launched startup company, Emulate, Inc. has licensed the technology and is now further developing and commercializing the Institute’s Organ Chip technology and automated instruments to bring these important research tools to biotechnology, pharmaceutical, cosmetics and chemical companies as well as academic institutions and hospitals for personalized medicine. Organ Chips are now being explored worldwide as tools for accurately predicting drug efficacies and toxicities, with the goal of dramatically improving the accuracy and efficiency of preclinical drug testing.

1/7 A system that links two Blood-Brain Barrier (BBB) Chips to a Brain Chip allows scientists to study how the brain and it's blood vessels influence each other.

2/7 The Lung-on-a-Chip offers an in vitro approach to drug screening by mimicking the complicated mechanical and biochemical behaviors of the human lung.

3/7 Lung-on-a-Chip sitting on a microscope, connected to vacuum and flow channels.

4/7 The Organs-on-Chips are crystal clear, flexible polymers about the size of a computer memory stick that contain hollow channels fabricated using computer microchip manufacturing techniques. These channels are lined by living cells and tissues that mimic organ-level physiology.

5/7 High resolution scan of a Gut-on-a-Chip.

6/7 The human gut-on-a-chip precisely mimics the biochemical and mechanical microenvironment of the human intestine, even expanding and contracting cultured human intestinal epithelial cells just as they would do rhythmically inside the gut through the process of peristalsis, as seen here. It is an ideal platform for studying the gut, the gut microbiome that thrives inside it, and for developing innovative new therapies to treat infection and disease of the intestinal tract.

7/7 Patent drawing of original Lung-on-a-Chip design. Next

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Current work at the Wyss Institute is now focused on developing specific human disease models and leveraging the Organ Chip platform with a novel computational discovery platform to identify new therapeutics and clinical biomarkers, facilitate vaccine development, and develop novel organ-specific drug delivery systems. In addition, Wyss researchers are exploring the potential of the technology for personalized medicine by engineering human stem cells that differentiate into highly functional specialized cell types on chips. They are also investigating the use of digital manufacturing to automate the fabrication of Organ Chips and increase the complexity of the devices, as demonstrated by the development of the first entirely 3D-printed organ-on-chip – a Heart Chip – with integrated soft strain sensors.

The Wyss Institute is currently seeking partners in their ongoing research and development efforts towards the creation of novel technologies for therapeutics discovery, organ-specific targeting, drug delivery, and clinical biomarkers.