Isabella Backman

Yale researchers have built a 3D-bioprinted synthetic aorta that they have successfully implanted into rats. This technology could advance the treatment of cardiovascular diseases such as coronary artery disease or peripheral arterial disease by allowing scientists to engineer and replace blood vessels in humans. The team recently published their findings in 

Through this new approach, scientists could use an individual’s own cells, or cells from a donor, to rapidly create custom-designed tissues that match the size and shape of the parts of vasculature to be replaced. Current treatments for severe cardiovascular disease include the use of grafts made from a patient’s own tissues (autologous) or synthetic materials. However, autologous grafts require invasive surgery and have a significant failure rate, and synthetic grafts are limited to large blood vessels and prone to leakage and harmful bacterial colonization.

Bioprinted vasculature could offer a better solution.

“This would be another alternative for people who are suffering from cardiovascular disease that allows them to maintain a higher quality of life,” says 

, professor emeritus of surgery (gastrointestinal) and of cellular and molecular physiology, and the study’s principal investigator.

A new proof-of-concept of bioprinted vasculature

Previously, scientists have tried to bioengineer tissues using a bioreactor, a chamber with a porous tube at its core into which they would inject the cells. The major downside of this method is that it is time-consuming—it can take weeks to create viable tissues.

In the new study, the researchers investigated the feasibility of bioprinting aortas. They cultured the main cells that make up the aorta—aortic cells, smooth muscle cells, and fibroblasts—from rats. Then, they loaded syringes into the bioprinter, which ejected these cells onto a rolling stainless-steel tube. After letting the cells incubate for a couple of days, the bioprinted aortas were ready for implantation.

The researchers tested their synthetic vascular structures in 20 rats. Twenty additional rats underwent the same surgical procedure without the implantation of the aorta. Rats in both groups resumed normal behavior following surgery and remained in good health. Notably, the procedure was also successful in rats who received aortas built from the cells of a different animal.

This is proof-of-concept of using bioprinted vasculature to treat cardiovascular diseases, the team says. “You might think it’s a far stretch from a rat to a human, but it isn’t,” says Geibel. “It’s just a matter of sizing—humans will require a lot more cells.”

The potential to use cells from a donor could help further reduce the time a patient waits to receive a bioprinted vessel. “Theoretically, we wouldn’t need to collect the cells from the patient with a cardiovascular disease,” Geibel says. “We could collect them from another individual and begin culturing them so that we have enough cells ready to go.”

The ability to bioprint human vasculature within days could have lifechanging implications, Geibel says. People with diabetes-related foot conditions, for instance, often have poor circulation that reduces blood flow to the feet. If left untreated, an amputation can be necessary. Custom-made blood vessels could be a new treatment for the condition that can help save the foot.

“You know the old adage—'one small step for a man, one giant leap for mankind,’” Geibel says. “This is the first step to get us toward technology in the future that will allow us to change how we help patients in a way that is dramatic.”

Articles

Yale researchers have developed a 3D-bioprinted synthetic aorta, successfully implanted in rats, potentially revolutionizing cardiovascular disease treatment. This technology enables the engineering and replacement of blood vessels using an individual's or donor's cells, offering a promising alternative to current grafts, which have limitations and risks. The bioprinting process is faster than traditional methods, producing viable tissues in days. This advancement could significantly improve patient outcomes, particularly for those with conditions like diabetes-related foot issues, by providing custom-made blood vessels to enhance circulation and prevent amputations.

Yale researchers unveil a groundbreaking 3D-bioprinted synthetic aorta, promising revolutionary advancements in cardiovascular disease treatment and patient care.

Bioprinted Aorta Shows Promise for Cardiovascular Disease Treatment

Researchers have identified a mechanism underlying insulin resistance in adolescents with obesity. The findings, published in 

, present a targetable pathway that could one day allow clinicians to intervene and prevent the onset of type 2 diabetes.

The number of youths with obesity has skyrocketed over the past several decades, and in turn, so have diseases previously associated with older age groups, such as heart disease and type 2 diabetes.

Adolescence is an especially vulnerable time in life to develop type 2 diabetes.
Nicola Santoro, MD, PhD

In a new study, Yale researchers observed how adolescents with obesity responded to insulin. Typically, insulin halts fat breakdown in adipose tissue—the connective tissue commonly known as “body fat.” But the researchers found that in adolescents who were insulin-resistant, insulin’s ability to block fat breakdown was impaired compared with those without insulin resistance.

“If fat cells don’t respond to insulin by stopping this breakdown process, the fat gets secreted into other tissues and causes a whole host of diseases,” explains Aaron Slusher, PhD, former associate research scientist at Yale School of Medicine (YSM) and the study’s first author.

Future medications that target this pathway and block the fat secretion from the liver could potentially prevent insulin-resistant adolescents from developing type 2 diabetes, the authors say.

“Adolescence is an especially vulnerable time in life to develop type 2 diabetes,” says 

, associate professor of pediatrics at YSM and the study’s second author. “Our study is a big step forward in understanding how insulin works—and how when it is not working correctly in fat tissue, it can lead eventually to type 2 diabetes.”

The findings follow previously made discoveries from preclinical animal research conducted by 

, George R. Cowgill Professor of Medicine (Endocrinology) at YSM and co-author of the study.

“Stopping the flux of fat from adipose tissue to other tissues would be key to reduce the rates of the cardiometabolic complications of obesity,” Santoro says.

Lipolysis is not suppressed in youth with obesity

For the study, the researchers took biopsies of the layer of adipose tissue beneath the skin from 30 adolescents with obesity—17 of whom were insulin-resistant—before and during infusions of insulin. They excluded potential participants if they had previously been diagnosed with type 2 diabetes.

Sonia Caprio, MD (left); Nicola Santoro, MD, PhD (center); and Gerald Shulman, MD, PhD (right)

To determine insulin resistance, they used an oral glucose tolerance test—a clinical test that is typically used to diagnose prediabetes and diabetes and involves measuring blood sugar levels before and after drinking a glucose solution. Subjects whose blood glucose levels took longer to return to normal were classified as insulin-resistant.

The team took the biopsies both before and after two insulin infusions—the first at a low concentration of insulin for two hours, followed by a second, higher concentration for an additional two hours. Meanwhile, the researchers looked for proteins associated with lipolysis—the process through which the body breaks down fat.

“When the participants initially came into the lab, they had done an overnight fast,” says Slusher. “When you’re in a fasted state, your fat cells are undergoing a process in which they allow fat to be excreted so that it can travel around and provide energy to other parts of the body. Insulin infusion mimics a signal to the body that it has been fed, which typically stops lipolysis and facilitates the storage of fat.”

In adolescents who were insulin-resistant, insulin was unable to inhibit the breakdown of fat, largely because insulin failed to activate the main enzyme regulating fat breakdown in adipose tissue. As a result, excess fatty acids continued to flow into other tissues, which may help explain why some adolescents with obesity develop type 2 diabetes.

“We are seeing a well-characterized mechanism respond differently in two distinct populations of children with obesity,” Slusher says.

Future research focuses on type 2 diabetes prevention

, professor of pediatrics (endocrinology) at YSM and senior author of the study, began treating children in the early ’90s, childhood obesity was not common. “But little by little, we saw an increase in the prevalence of obesity—and it became very concerning to us,” she says. “By the beginning of the 2000s, we realized kids were being diagnosed with type 2 diabetes, which was—at least in our clinic—previously unheard of.”

The team hopes their identification of this altered mechanism can help researchers better understand how to therapeutically intervene.

I want to stop the onset of type 2 diabetes—that’s our goal.
Sonia Caprio, MD

“We can see if interventions—such as dietary changes or physical activity interventions, or perhaps a new pharmacologic agent—impact this target favorably,” says Slusher. “Then, we can hopefully design a strategy to make these youth more sensitive to insulin signaling and mitigate negative downstream consequences.”

Caprio’s laboratory is currently studying how drugs such as semaglutide—currently used for weight loss and treating type 2 diabetes—improve insulin sensitivity and prevent type 2 diabetes in youth. “I want to stop the onset of type 2 diabetes—that’s our goal,” she says.

The research reported in this news article was supported by the National Institutes of Health (awards R01HD02801625A1, T32DK007058, R01DK124272, RO1DK119968, R01MD015974, RO1DK113984, P3DK045735, RO1DK133143, and RC2DK120534) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.

Researchers have identified a mechanism contributing to insulin resistance in adolescents with obesity, offering a potential target for preventing type 2 diabetes. The study observed impaired insulin function in halting fat breakdown in insulin-resistant adolescents, leading to excess fatty acids entering other tissues. This discovery could guide future interventions, including medications, dietary changes, or physical activity, to enhance insulin sensitivity. The research, supported by the National Institutes of Health and Yale University, aims to mitigate the rising incidence of type 2 diabetes in youth.

Researchers uncover a mechanism of insulin resistance in obese adolescents, paving the way for potential interventions to prevent type 2 diabetes.