Microsystems with a big impact

Research uses new polymer chip model to grow biomimetic microtissue

Jim Cirigliano
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STARKVILLE, Miss.—Mississippi State University researcher Renita Horton, assistant professor of biomedical engineering, is developing new models using clear polymer “chips” to culture cellularized microtissue in an effort to better understand the factors that lead to heart disease and sickle cell anemia.
Cellularized microtissue models allow researchers to study the cellular mechanisms that drive progression of various diseases. These systems are simple organ models, often consisting of one or two types of cells. In Horton’s models, cardiovascular cells segmented into biomimetic microsystems in clear polymer “chips” are used to model and predict heart tissue’s response to various stimuli.
“These chips serve as a platform to grow microtissues,” says Horton. “We can recapitulate features of the microenvironment. Using these model systems, we can probe how cells and microtissues respond to various perturbations. We can also introduce cells to flow similar to blood flow experienced in vivo, which is a benefit over traditional cell culture.”
Horton’s research is focused on exploring heart disease and sickle cell anemia, specifically. Her models will begin by culturing and examining cardiomyocytes, the cells that cause the heart to beat, within the chips. This way, Horton will examine environmental factors that lead to vaso-occlusions, a painful complication of sickle cell anemia, and other mechanisms that contribute to organ damage in sickle cell patients. The cultured cardiovascular cells can then be treated with various drugs to observe the effects.
“We know that many different cells make up the heart and make it function, but with heart disease, we’re really interested in when the heart starts to dysfunction,” Horton said in a media release announcing the research endeavor. “In our case, we start by manipulating cardiomyocytes to understand how they respond to changes in the microenvironment to enhance our understanding of disease onset.”
As the research progresses, Horton says she anticipates building more complexity into their system to more closely mimic the entire organ.
“We aim to improve the current knowledge surrounding disease mechanisms related to cardiovascular-related diseases,” says Horton. “These chips allow us to manipulate the cellular environment to better disease onset and progression. Furthermore, they can potentially be used for drug testing on cells derived from various organs.”
In-vitro models such as those used in Horton’s research can serve to reduce the need for animals in biomedical research. A positive or adverse effect in a microtissue model can suggest a similar effect may be observed in the entire organ.
“The body is a multifaceted system,” Horton adds. “Events that happen in one organ can potentially affect the function of another organ. These complex signals can be difficult to mimic in vitro. However, the fact that we can culture human-derived cells can potentially provide more accurate predictions over animal-based systems.”
The ultimate goal of this research is to provide practical benefits for patients and improve patient outcomes by first understanding cardiovascular disease onset and then identifying novel therapeutic targets. Horton says that her team hopes to uncover novel mechanisms that trigger disease by mimicking features of disease on their chip platform. They can subsequently test their ability to improve cell function by treating with potential drug candidates.
Horton established MSU’s Cardiovascular Tissue Engineering Laboratory in 2016 after completing a postdoctoral fellowship at Harvard University’s Wyss Institute for Biologically Inspired Engineering. She and a half dozen undergraduate and master’s students in MSU’s Department of Agricultural and Biological Engineering work in the lab designing biomimetic microsystems that mimic features of specific organs to predict the organs’ response to stimuli.
Although cellularized microdevices are not a new concept, the devices are subject to constant improvements. Horton’s lab at MSU is one of several facilities currently working with vascular-related microtissue models. In April, researchers at Virginia Polytechnic Institute and State University (Virginia Tech) published a study titled “3D Microtissue Models to Analyze the Effects of Ultralow Dose LPS on Vascular Sprouting Dynamics in the Tumor Microenvironment.”
The study similarly used a microenvironment model, in their case to test tumor progression in response to low-dose exposure to lipopolysaccharide (LPS), which plays a role in the body’s innate immune responses. This study used a 3D collagen hydrogel tissue mimic to assess the effects of chronic inflammation on the vascular dynamics of tumors.
LPS is known to affect tumor progression when present in high concentrations but its effects when present in lower levels are unclear. Ultra-low levels of LPS (<100 pg/mL) are present in the body during states of chronic inflammation, and the study used advanced imaging and cell characterization assays to assess alterations in the vascular response to low- versus high-dose LPS in the context of tumor progression.
The study found enhanced vascular development of human brain microvascular endothelial cells (HBMECs) in their in-vitro microenvironmental model with the treatments of ultra-low dose LPS, accounting for frequency of sprouting and the invasiveness of the sprouts. The results suggest a potential link between chronic inflammation—specifically the resultant ultra-low levels of LPS—and contributions to tumor progression.

Jim Cirigliano

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