MIT engineers have developed new
technology that could be used to evaluate new drugs and detect possible side
effects before the drugs are tested in humans. Using a microfluidic platform
that connects engineered tissues from up to 10 organs, the researchers can
accurately replicate human organ interactions for weeks at a time, allowing
them to measure the effects of drugs on different parts of the body.
Such
a system could reveal, for example, whether a drug that is intended to treat
one organ will have adverse effects on another.
"Some
of these effects are really hard to predict from animal models because the
situations that lead to them are idiosyncratic," says Linda Griffith, the
School of Engineering Professor of Teaching Innovation, a professor of
biological engineering and mechanical engineering, and one of the senior
authors of the study. "With our chip, you can distribute a drug and then
look for the effects on other tissues and measure the exposure and how it is
metabolized."
These
chips could also be used to evaluate antibody drugs and other immunotherapies,
which are difficult to test thoroughly in animals because they are designed to
interact with the human immune system.
David
Trumper, an MIT professor of mechanical engineering, and Murat Cirit, a
research scientist in the Department of Biological Engineering, are also senior
authors of the paper, which appears in the journal Scientific Reports. The paper's lead
authors are former MIT postdocs Collin Edington and Wen Li Kelly Chen.
Modeling
organs
When
developing a new drug, researchers identify drug targets based on what they
know about the biology of the disease, and then create compounds that affect
those targets. Preclinical testing in animals can offer information about a
drug's safety and effectiveness before human testing begins, but those tests
may not reveal potential side effects, Griffith says. Furthermore, drugs that
work in animals often fail in human trials.
"Animals
do not represent people in all the facets that you need to develop drugs and
understand disease," Griffith says. "That is becoming more and more
apparent as we look across all kinds of drugs."
Complications
can also arise due to variability among individual patients, including their
genetic background, environmental influences, lifestyles, and other drugs they
may be taking. "A lot of the time you don't see problems with a drug,
particularly something that might be widely prescribed, until it goes on the
market," Griffith says.
As
part of a project spearheaded by the Defense Advanced Research Projects Agency
(DARPA), Griffith and her colleagues decided to pursue a technology that they
call a "physiome on a chip," which they believe could offer a way to
model potential drug effects more accurately and rapidly. To achieve this, the
researchers needed new equipment -- a platform that would allow tissues to grow
and interact with each other -- as well as engineered tissue that would
accurately mimic the functions of human organs.
Before
this project was launched, no one had succeeded in connecting more than a few
different tissue types on a platform. Furthermore, most researchers working on
this kind of chip were working with closed microfluidic systems, which allow
fluid to flow in and out but do not offer an easy way to manipulate what is
happening inside the chip. These systems also require external pumps.
The
MIT team decided to create an open system, which essentially removes the lid
and makes it easier to manipulate the system and remove samples for analysis.
Their system, adapted from technology they previously developed and
commercialized through U.K.-based CN BioInnovations, also incorporates several
on-board pumps that can control the flow of liquid between the
"organs," replicating the circulation of blood, immune cells, and
proteins through the human body. The pumps also allow larger engineered
tissues, for example tumors within an organ, to be evaluated.
Complex
interactions
The
researchers created several versions of their chip, linking up to 10 organ
types: liver, lung, gut, endometrium, brain, heart, pancreas, kidney, skin, and
skeletal muscle. Each "organ" consists of clusters of 1 million to 2
million cells. These tissues don't replicate the entire organ, but they do
perform many of its important functions. Significantly, most of the tissues
come directly from patient samples rather than from cell lines that have been
developed for lab use. These so-called "primary cells" are more
difficult to work with but offer a more representative model of organ function,
Griffith says.
Using
this system, the researchers showed that they could deliver a drug to the
gastrointestinal tissue, mimicking oral ingestion of a drug, and then observe
as the drug was transported to other tissues and metabolized. They could
measure where the drugs went, the effects of the drugs on different tissues,
and how the drugs were broken down. In a related publication, the researchers
modeled how drugs can cause unexpected stress on the liver by making the
gastrointestinal tract "leaky," allowing bacteria to enter the
bloodstream and produce inflammation in the liver.
Griffith
believes that the most immediate applications for this technology involve
modeling two to four organs. Her lab is now developing a model system for
Parkinson's disease that includes brain, liver, and gastrointestinal tissue,
which she plans to use to investigate the hypothesis that bacteria found in the
gut can influence the development of Parkinson's disease.
Other
applications include modeling tumors that metastasize to other parts of the
body, she says.
"An
advantage of our platform is that we can scale it up or down and accommodate a
lot of different configurations," Griffith says. "I think the field
is going to go through a transition where we start to get more information out
of a three-organ or four-organ system, and it will start to become
cost-competitive because the information you're getting is so much more
valuable."
Source:
https://www.sciencedaily.com/releases/2018/03/180314092314.htm
