3D-printed microfluidic devices that model the blood-brain barrier in Prof. Samara M. Azarin’s lab. (S. Azarin)
University of Minnesota researchers are at the leading edge of "organ-on-a-chip" technology, which they are using to examine the effects of low- and medium-dose radiation exposure on different tissues in the human body. Professor Angela Panoskaltsis-Mortari is working with colleagues at the University and at the Uniformed Services University (USU) on a project that has implications for military personnel who might be exposed to radiation on the battlefield as well as for people exposed to civilian nuclear accidents and cancer patients who undergo radiation treatment.
“When someone is right near the site of a nuclear accident like Chernobyl or Fukushima, we know about the significant damage that that exposure can cause to people’s bodies,” said Panoskaltsis-Mortari. “We have a lot less information about what happens to people’s internal organs when they are a little more removed and are exposed to lower doses of radiation."
The project uses 3D biological models of organs to simulate the effects of radiation exposure on the lungs, the heart, and the brain at the blood-brain barrier, exploring the potential for various drugs to be able to treat those types of injuries and whether they mitigate the effects of the damage and help repair the tissue if given either before—if someone knew they could potentially be exposed—or after an exposure.
Unlocking New Frontiers: 3D Bioprinting and Biological Models
About a decade ago, Panoskaltsis-Mortari was working on cell therapies and bioengineering approaches that could help heal lung injuries and she came across the new technology of 3D bioprinting, where 3D printers use biological materials as their building material instead of synthetic filaments.
“I realized that not only could this new technology be used to create three-dimensional tissue for implantation and transplantation purposes, but it could also be used to create small three-dimensional models to study disease and biology, and to screen potential drugs for toxicity and for treating disease,” she said. Today, in addition to serving as vice chair for research and a professor in the Medical School’s Department of Pediatrics in the Division of Blood and Marrow Transplantation & Cellular Therapy, she is also the director of the University of Minnesota 3D Bioprinting Facility.
3D bioprinting has helped solve some of the limitations of traditional cell studies, which are usually done on a flat surface on plastic dishes and lack the complex 3D environment that cells in the body actually live in, and animal models, which sometimes do not extrapolate to what happens in the human body.
“The idea is that you would make these small three-dimensional models that would be more physiologically relevant,” she said. “It wouldn't mimic the tissue entirely, of course—it's still a model—but I have found that a lot of the time when you introduce a drug or something in a three dimensional model, it better mimics the timing of how it happens in the body as opposed to doing it on a 2D flat surface.”
These small 3D models are often called organs on a chip, because they are small—but still mostly visible to the naked eye—self-contained systems where a researcher can test how a biological system made up of living cells reacts to new inputs. Amidst an exponential growth of organ-on-a-chip technologies in the last decade, Panoskaltsis-Mortari and her colleagues are particularly interested in simulating tissues that are usually in motion, such as the lungs and the heart.
“I think our systems are more dynamic than that. For example, for the lungs, in our model we've introduced ventilation. Because the lungs expand, that affects how the cells behave since cells respond to the stiffness of their environment as well as to stretch, she said. “Then in the heart, of course, the heart is contracting all that muscle, and you wouldn't be able to do that on the conventional types of organ-on-a-chip models. So our models are different. They are more 3D than the typical organ-on-chip-models, but they are still modular.”
Body-on-a-Chip: Integrating Lungs, Heart, and the Blood-Brain Barrier
Panoskaltsis-Mortari is leading work on the lung model. University of Minnesota biomedical engineering professor Brenda Ogle is developing the heart model component for the project, which will be connected to the lung component and the blood-brain barrier component by a shared nutrient supply. Ogle says that the idea of integrating multiple tissue types into a single system into a “body on a chip” model is not new, but that she and her colleagues are designing their “chip” model specifically for radiation exposure.
“This exercise has really helped us better define the key metrics in this system and also how we can apply it not just for radiation exposure out in the field, but radiation exposure in occupations, cancer treatment, and more,” Ogle said.
Instead of 3D bioprinting, Ogle’s organ on a chip uses stem cell-derived cardiac cells to form microtissues mimicking heart function. The engineered component is a five-millimeter strip (approximately the size of pencil-top eraser) of cardiac muscle tissue suspended between two stationary pillars, providing passive resistance against which the specialized cells, called cardiomyocytes, can spontaneously beat.
Samira M. Azarin, associate professor of chemical engineering and materials science, is using both 3D bioprinting and cultured stem cells for her model of the blood-brain barrier. This barrier, comprising blood vessels formed by brain-specific endothelial cells, is a key part of how the body keeps the brain safe from potentially harmful compounds in the blood, although it also often blocks potentially helpful drug molecules from entering the brain. Azarin’s project uses 3D bioprinting to create a semi-permeable membrane on which stem-cell derived brain endothelial cells are cultured. On the other side of the membrane is a 3D hydrogel containing cells such as astrocytes and pericytes that mimic the brain tissue underlying the barrier.
Testing and Validation: The USU and AFRRI Collaboration
Once the three components and the model have been finalized, Panoskaltsis-Mortari and her colleagues will transfer the technology to their colleague Vincent B. Ho, chair and professor of the Department of Radiology and Bioengineering and Director of the USU Center for Biotechnology (4DBio3) at USU, who will do the radiation exposure at secure and contained facilities of the Armed Forces Radiobiology Research Institute (AFRRI). In addition to collaborating in development of these organ-on-chip platforms, Ho and his colleagues will also validate the organ-on-a-chip models by evaluating the efficacy of two existing anti-radiation drugs in preventing and healing radiation damage.
The organ-on-a-chip collaboration with USU is one of 24 joint projects between the University and USU, as well as Fairview Health Systems and Medical Alley, a collaboration funded by congressional appropriations in 2022 and 2023 championed by Minnesota members of Congress, including Congresswoman Betty McCollum, a senior member of the House Subcommittee on Defense Appropriations.
When asked about her experience working with USU, Ogle was complimentary.
“It's been incredibly fruitful to be able to collaborate directly with Uniformed Services University because they have such immediate contact and context for what is needed by people in the military who potentially face a radiation threat,” Ogle said. “So it's number one, effective. Number two, it has led to the development of our technology in a way that has become or will become multifaceted and applicable to many other areas, especially to basic biology and medical advances.”
The USU collaboration is helping inform Ogle’s efforts to “lead the charge” to create simple organ-on-a-chip models that can be mass-produced on campus, and then distributed to help academic research labs, and pharmaceutical and medical device companies assess the efficacy of potential drugs and medical devices. The models could help reduce the need for expensive pre-clinical research with animals in an era when the National Institutes of Health is trying to reduce reliance on animal models, optimize the compounds and dosages for animal studies that are necessary, and even help researchers have a similar, optimized starting point for drug and device trials in humans. Overall, the effort could help speed up the development of safe and effective drugs and device interventions.
“Our concept is to build a national facility with the capacity to make organ-on-a-chip models—typically made in small batches in siloed research laboratories—more broadly accessible. The facility will drive the scaled production, preservation, storage and distribution of such testbeds,” she said.
University of Minnesota faculty and staff interested in DoW and other national security agency support can visit the University’s National Security Research Institute to learn more.
Disclaimer: The opinions and assertions expressed herein are those of the authors and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of War.
COI Disclaimer: Neither persons in this collaboration nor their families have a financial interest in any commercial product, service, or organization providing financial support for this research.