Researchers have successfully created a platform that mimics the natural environment of human bone marrow. This innovation is significant in medical research, particularly because animal studies often do not capture the complex characteristics of human marrow.
Bone marrow, found within our bones, plays a crucial role by producing billions of blood cells each day—inclusive of red cells that transport oxygen and white cells that bolster our immune system. However, this essential function can be compromised in cancer patients who undergo treatments like chemotherapy or radiation, which can harm the marrow and result in dangerously low levels of white blood cells, heightening the risk of infections.
Now, a team from the University of Pennsylvania’s School of Engineering and Applied Science (Penn Engineering), the Perelman School of Medicine (PSOM), and the Children’s Hospital of Philadelphia (CHOP) has developed a new platform that accurately represents the native conditions of human marrow. This advancement fills a vital gap in medical research, where traditional animal studies often miss the nuances of human marrow.
Mimicking Human Marrow
The new device designed by the researchers is a compact plastic chip containing specially crafted chambers filled with human blood stem cells along with the support cells that interact with them in a hydrogel. This setup mimics the complex process of bone marrow development that occurs during human embryonic growth. This innovative system facilitates the creation of living human marrow tissue that can produce viable human blood cells and release them into culture media flowing through engineered capillary blood vessels.
The bone marrow-on-a-chip technology enables researchers to replicate and evaluate common side effects associated with medical treatments such as radiation and chemotherapy in cancer therapy. When connected to another device, it can even simulate how bone marrow communicates with other organs like the lungs, helping shield them from infections and other severe conditions.
Described in a recent publication in Cell Stem Cell, this bone marrow model, along with its ability for large-scale production and automation, could progress various fields—including drug development through automated, high-throughput preclinical assessments of anticancer drug toxicity, and space exploration, where it can assist in observing the effects of extended periods of radiation exposure and microgravity on astronauts’ immune systems.
“Our ability to regenerate human tissues in vitro and imitate their complex functions has advanced significantly, but I believe this system ranks among the most advanced bioengineered tissue models created thus far,” shares Dan Huh, a Bioengineering Professor and the paper’s senior author. “For instance, we demonstrate for the first time the potential to create interlinked organ-on-a-chip models that represent human marrow and bacterially-infected lungs, capturing the biochemical interactions between these two organs and the entire innate immune response process to an infection, including the rapid deployment of a massive number of white blood cells from the marrow into the bloodstream, and their navigation into the infected airways to combat infection by engulfing bacteria.”
Extraterrestrial Origins
This project initially aimed to analyze the immune system in space. Nearly a decade ago, Huh, alongside G. Scott Worthen, a physician at CHOP and a Professor Emeritus in Pediatrics at PSOM, proposed developing a human bone marrow model to send to the International Space Station (ISS). “Given the increasing evidence of a heightened infection risk for astronauts on extended missions, we wanted to investigate how weightlessness impacts our immune system,” explains Worthen. “We hypothesized that microgravity might have negative effects.”
Regrettably, the researchers could not complete their planned experiments on Earth and the ISS for comparison. “Unfortunately, the flow controller of the cubelab system needed to sustain our engineered tissue models malfunctioned during launch,” recalls Huh. “And the second launch was canceled due to the pandemic.”
Nevertheless, the capabilities of the new chip proved to be extensive. “Despite our failed space experiments, this project has been one of the most fulfilling experiences in my research career. It excites me that by utilizing this system, we can now replicate some of the fundamental features of human marrow and our immune system. I believe this new technology marks a significant advancement that will pave the way for deeper exploration of human hematopoiesis and innate immunity,” states Huh.
Borrowing Nature’s Recipe
Bone marrow consists of several key components, such as hematopoietic stem cells (HSCs), which develop into various blood cell types; endothelial cells, which form blood vessel walls; and mesenchymal cells, which build and support the marrow’s connective tissue.
Previously, attempts to combine these components were made, but researchers struggled to accurately reproduce the structure and function of real human marrow. “Every organ in the human body is intricate, but the unique biological characteristics and inaccessibility of human bone marrow make it particularly challenging to model and study its physiology in vitro,” notes Huh.
The crucial breakthrough was concentrating on how human embryos naturally develop bone marrow. During fetal development, multiple overlapping processes guide bone marrow growth, driven by a few key cell types that “self-organize” in response to environmental stimuli, ultimately forming clusters of stem cells within a dense vascular network that transports new cells throughout the body.
Determining the optimal conditions to culture these cell types fell to Andrei Georgescu (GEng’21), a former PhD student in Huh’s lab who now leads Vivodyne, a startup he co-founded with Huh to promote organ-on-a-chip technology. “Our design approach is unique because it relies on stem and progenitor cells’ talent to self-organize and assemble into complex tissues,” says Georgescu. “This means that when grown in the ‘right’ environment, these cells can construct realistic tissues with physiological attributes. Finding these ideal conditions required extensive effort.”
Towards the Holy Grail of Cell Therapy
One significant discovery from this research revealed that the marrow chip can not only generate blood cells but also create an environment that supports the maintenance of hematopoietic stem and progenitor cells for long durations. This indicates the chip could help scientists understand the biological signals required to sustain or even expand hematopoietic stem cells taken from human donors through expensive and invasive medical procedures. “Given the importance of hematopoietic stem cell transplantation in treating various diseases, exploring how our technology can be applied to HSC-based cell therapies is a major goal for our future research,” concludes Huh.
This study was conducted at the University of Pennsylvania’s School of Engineering and Applied Science and was funded by the National Institutes of Health (grants 1DP2HL127720-01 and 1UG3TR002198-01), the National Science Foundation (CMMI:15-48571), the Paul G. Allen Foundation, the GRDC Cooperative Hub (RS-2023-00259341) via the National Research Foundation of Korea, the Ministry of Science and ICT, the Bio Industrial Technology Development Program (20018463) funded by the Ministry of Trade, Industry, and Energy, the University of Pennsylvania, and the National Center for Advancing Translational Sciences (KL2TR001879).
Other co-authors include Samira Mehta, Pouria Fattahi, Anni Wang, Sezin Aday Aydin and Jeongyun Seo from Penn Engineering; Joseph Hai Oved from CHOP and PSOM; Jonathan H. Galarraga and Thomas Cantrell from Vivodyne; Brian M. Dulmovits and Timothy S. Olson from CHOP; Pelin L. Candarlioglu, Asli Muvaffak and Anthony Lynch from GlaxoSmithKline; and Michele M. Kim and Eric S. Diffenderfer from PSOM.
