Gordana Vunjak-Novakovic Opens BMES Annual Meeting

This is the fifth in a series of articles highlighting some of the technologies, processes and keynote plenary sessions presented at the 2024 Annual Meeting of the Biomedical Engineering Society, October 2024. 

Introduced as simply "Gordana" because her work in bioengineering is so well known, Gordana Vunjak-Novakovic opened the 2024 BMES Annual Meeting with a lecture entitled, “Translational studies of engineered human tissues.” It proved a powerful reminder of just how far the field has come in a scant 20 years. 

Vunjak-Novakovic is a University Professor of Biomedical Engineering at Columbia University and 2017 winner of the BMES’ Robert A. Pritzker Distinguished Lectureship Award. She has also founded four companies. Her talk covered research breakthroughs that ranged from artificial bone to placing multiple organs on a chip to better model organ interactions during disease.  

Her work, she emphasized, always starts with the cell. “The key player in any tissue engineering recipe is the cell,” she said. “Cells are the builders of tissues. 

“Cells are really smart,” she continued. “They are responsive, so you have to give them the right clues and then they will take care of the rest.”  

Vunjak-Novakovic provides those clues with scaffold materials that mimic the physical environment where the desired cells grow in the body. She also builds sophisticated bioreactors to study cell and tissue behavior over days and weeks. Her lab, in fact, is home to NIH’s National Tissue Engineering Resource Center and its Bioreactor Core. 

Building bones and repairing organs 

Vunjak-Novakovic began working on artificial bone 20 years ago, after moving from MIT to Columbia University. She was looking for an ambitious project for a graduate student and decided she should try to mimic the anatomy and biological function of natural bone.  

“The big challenge was the bioreactor itself and understanding how to optimize its design to ensure perfusion of nutrients to support vigorous, even growth,” she said. “It took lots of redesigns to get it right.” 

The investigators developed liquid culture media with the right balance of nutrients, oxygen, and other factors. They learned to manipulate the force and shear of its flow to produce flat and curvy structures. Eventually, they even learned to grow fully functional cartilage over the bone.  

She chose the body's most complex and heavily loaded bone, the lower jaw, for a test. Her team carved out a space in a healthy jaw and filled it with partially functional bone. Within six months, the smooth bioengineered edge of the bone looked and behaved like a natural bone. Vunjak-Novakovic spun off a company, EpiBone, to develop the technology commercially. 

Her next project came about when a visiting surgeon mentioned that there were not enough donors for lung transplants. Even then, most donor lungs are not in good enough shape to support a patient and had to be thrown away. 

Growing new lungs was out of the question. Lungs contain at least 50 distinct types of cells, structured in a hierarchical series of branching airways and blood vessels. This gives the average lung about 145 square meters of gas exchange surface, equivalent to three-quarters of a singles tennis court. Instead of building a lung, Vunjak-Novakovic wondered if she could repair one. 

The procedure her team developed starts by removing defective lung cells. They did this in a way that preserved the composition, architecture, and mechanical properties of the extracellular matrix, surrounding tissue, and vasculature.  

The investigators then placed the lung in a bioreactor. Through cross-circulation, they link the lung to the patient's bloodstream. This enables the patient's own bloodstream to deliver factors that regenerate lung tissue and blood vessels while reducing inflammation and clearing debris through the patient's own kidneys and liver. 

Her lab has shown that it can repair lungs within two or three days so that they are good enough to use as transplants. The team recently showed it could support those lungs for as long as 100 hours.  

Vunjak-Novakovic is also using the same tools to study the roles of cells and extracellular matrix in the initiation and progression of pulmonary fibrosis.  

Another research thrust is to regenerate cardiomyocytes, cells that cause the heart to contract and release. When these cells are lost due to injury, such as a heart attack, the body cannot regenerate them. While researchers can grow cardiomyocytes from stem cells, the resulting cells integrate poorly with existing heart muscle and often cause arrhythmia. Moreover, implanting those cells surgically is dangerous. 

Vunjak-Novakovic's solution is to use exosomes, small nanoscale vesicles released that communicate with other cells by carrying microRNAs and other biomolecules to them. Her team infuses hydrogels with exosomes carrying microRNA with signals to grow heart muscle.  

When injected into a rat with a damaged heart, they found the exosomes preserved heart function but did not revive or replace dead cells. It only worked when delivered shortly after a heart attack.  

Organs on a chip 

Much of Vunjak-Novakovic's recent work focuses on microphysiological systems, often called organs-on-a-chip. Her research grew out of an NIH initiative 12 years ago to test drugs and monitor disease progression by replacing animal models with human organoids. Investigators have long known that some drugs that work on small animals have no impact on humans, while potentially useful medicines go undiscovered when using animal models. Microphysiological systems--human organs on a chip--might produce more accurate results.  

Also, when grown from stem cells from a variety of people, these models could do a better job of reflecting the genetic diversity found in the human race.  

Vunjak-Novakovic's started by looking for ways to grow stable organoids that could survive for weeks or even months. This is especially difficult because researchers have not been able to recreate the blood vessels that supply natural organs with oxygen and nutrients. 

Her team has had some success. A new mature heart organoid, for example, shows excellent functional properties, such as electrical and calcium signaling and oxidative metabolism. Lab investigators are also making progress in vascularizing the model to make it thicker and more robust. 

While conducting these studies, Vunjak-Novakovic’s lab developed an organ-on-a-chip platform for their own studies. The advanced design included automation, improved imaging, and AI software.  

They are now making the easy-to-learn platform and software fully available to researchers in the field. “We published absolutely everything, all protocols, all software, everything that someone may need to make a platform, to build a tissue, and to characterize its properties,” Vunjak-Novakovic said. 

This technology proved itself clinically in the case of a two-year-old boy. He had a fatal disease that caused his heart to contract but not release. Researchers edited his stem cells to reproduce the mutation, then did a massive screening of potential drugs and found one that promised to save his life.  

The platform was also used to study why some lupus patients develop inflamed hearts and why this leads to advanced stage heart disease in only some of them. The study was able to classify the role of various lupus-related autoantibodies (proteins that attack the body’s own cells) so researchers could do further research on those most damaging to heart cells. 

Over the past 10 years, Vunjak-Novakovic has focused on developing mature multi-tissue organs-on-a-chip that were stable enough to survive for weeks or even months.  

The key challenge in building the platform was maintaining phenotype, the physical expression of an organ’s genes, Vunjak-Novakovic explained. To maintain phenotype, she must culture each tissue in its own microenvironment.  

Yet to create a chip with multiple interlinked tissues, diverse organoids must communicate with one another. This is done by allowing individual tissues compartments to communicate across a connective endothelium and through vascular perfusion.  

Another key to her research was developing a functional bone analog that could generate its own immune cells. This enabled her lab to study how the immune system interacted with cancer and other diseases.  

One example involves linking bone marrow tissue with breast cancer tissue. The investigators observed how the breast cancer cells skewed the production of cells in bone marrow, suppressing cells involved in immune response to create a more hospitable environment for the cancer. The researchers also found that bone marrow itself affects cancer cell dormancy and, under some conditions, growth.  

The lab also uses the multi-tissue platform to study why some lung cancers metastasize and others do not. 

Vunjak-Novakovic sees a bright future as our ability to create environments for cells and tissues expands in both fidelity and scale.  

“Studies are incredibly important for most diseases, and more and more, the advances that we make are driven not only by synthetic curiosity, but also by very specific needs,” she said.  

Fulfilling those needs is something that was far beyond our grasp even a single decade ago.