University of Toronto Engineering researchers have grown a small-scale model of a human left heart ventricle in the lab. The bioartificial tissue construct is made with living heart cells and beats strongly enough to pump fluid inside a bioreactor.

In the human heart, the left ventricle is the one that pumps freshly oxygenated blood into the aorta, and from there into the rest of the body. The new lab-grown model could offer researchers a new way to study a wide range of heart diseases and conditions, as well as to test out potential therapies.

“With our model, we can measure ejection volume — how much fluid gets pushed out each time the ventricle contracts — as well as the pressure of that fluid,” says Sargol Okhovatian. “Both of these were nearly impossible to get with previous models.”

Okhovatian and Mohammad Hossein Mohammadi are co-lead authors on a new paper in Advanced Biology that describes the model they designed. Their multidisciplinary team was led by Professor Milica Radisic, senior author of the paper.

All three researchers are members of the Centre for Research and Applications in Fluidic Technologies (CRAFT). A unique partnership between Canada’s National Research Council and the University of Toronto, CRAFT is home to world-leading experts who design, build and test miniaturized devices to control fluid flow at the micron scale, a field known as microfluidics.

“The unique facilities we have at CRAFT enable us to create sophisticated organ-on-a-chip models like this one,” says Radisic.

“With these models, we can study not only cell function, but tissue function and organ function, all without the need for invasive surgery or animal experimentation. We can also use them to screen large libraries of drug candidate molecules for positive or negative effects.”

Many of the challenges facing tissue engineers relate to geometry: while it’s easy to grow human cells in two dimensions — for example, in a flat petri dish — the results don’t look much like real tissue or organs as they would appear in the human body.

To move into three dimensions, Radisic and her team use tiny scaffolds made from biocompatible polymers. The scaffolds, which are often patterned with grooves or mesh-like structures, are seeded with heart muscle cells and left to grow in a liquid medium.

Over time, the living cells grow together, forming a tissue. The underlying shape or pattern of the scaffold encourages the growing cells to align or stretch in a particular direction. Electrical pulses can even be used to control how fast they beat — a kind of training gym for the heart tissue.

For the bioartificial left ventricle, Okhovatian and Mohammadi created a scaffold shaped like a flat sheet of three mesh-like panels. After seeding the scaffold with cells and allowing them to grow for about a week, the researchers rolled the sheet around a hollow polymer shaft, which they call a mandrel.

The result: a tube composed of three overlapping layers of heart cells that beat in unison, pumping fluid out of the hole at the end. The inner diameter of the tube is 0.5 millimetres and its height is about 1 millimetre, making it the size of the ventricle in a human fetus at about the 19th week of gestation.

“Until now, there have only been a handful of attempts to create a truly 3D model of a ventricle, as opposed to flat sheets of heart tissue,” says Radisic.

“Virtually all of those have been made with a single layer of cells. But a real heart has many layers, and the cells in each layer are oriented at different angles. When the heart beats, these layers not only contract, they also twist, a bit like how you twist a towel to wring water out of it. This enables the heart to pump more blood than it otherwise would.”

The team was able to replicate this twisting arrangement by patterning each of their three panels with grooves at different angles to each other.

In collaboration with Professor Ren-Ke Li’s lab within the University Health Network, they measured the ejection volume and pressure using a conductance catheter, the same tool used to assess these parameters in living patients.

At the moment, the model can only produce a small fraction — less than 5% — of the ejection pressure that a real heart could, but Okhovatian says that this is to be expected given the scale of the model.

“Our model has three layers, but a real heart would have eleven,” she says.

“We can add more layers, but that makes it hard for oxygen to diffuse through, so the cells in the middle layers start to die. Real hearts have vasculature, or blood vessels, to solve this problem, so we need to find a way to replicate that.”

Okhovatian says that in addition to the vasculature issue, future work will focus on increasing the density of cells in order to increase the ejection volume and pressure. She also wants to find a way to shrink or eventually remove the scaffold, which a real heart wouldn’t have.

Though the proof-of-concept model represents significant progress, there is still a long way to go before fully functional artificial organs are possible.

“We have to remember that it took us millions of years to evolve a structure as complex as the human heart,” says Radisic.

“We’re not going to be able reverse engineer the whole thing in just a few years, but with each incremental improvement, these models become more useful to researchers and clinicians around the world.”

“The dream of every tissue engineer is to grow organs that are fully ready to be transplanted into the human body,” Okhovatian.

“We are still many years away from that, but I feel like this bioartificial ventricle is an important stepping-stone.”

HOUSTON (Jul. 12, 2022) – Dr. Joshua Shulman, Professor at Baylor College of Medicine, has been named the new Co-Director of the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital. The Duncan NRI is a premier neurological research institution and a destination for families seeking answers and treatments for rare and undiagnosed neurological conditions, as well as for more common neurodegenerative and neuropsychiatric disorders.

“Dr. Shulman is one of those rare physician-scientists who possess exquisite clinical skills, compassion, scholarship, and innovation in research,” said Dr. Huda Zoghbi, Director of the Duncan NRI, Howard Hughes Medical Institute Investigator, and distinguished service Professor at Baylor. “These attributes, combined with his leadership and dedication to mentoring the next generation of scientists, make him ideal for the Co-Director role at the Duncan NRI. I am thrilled to partner with him as we continue to move forward addressing devastating neurological disorders.”

Dr. Shulman succeeds Dr. John Swann as the Co-Director of the Duncan NRI and brings with him 25 years of experience as a neuroscientist and adult neurologist specializing in Parkinson’s, Alzheimer’s, and other neurodegenerative disorders. He completed his medical and research training at Harvard Medical School, Massachusetts General and Brigham and Women’s Hospitals, and Cambridge University in the U.K. He was recruited to Baylor and the Duncan NRI in 2012 and is now a Professor in the departments of Neurology, Molecular and Human Genetics, and Neuroscience at Baylor. He is also the founding Director of Baylor’s Center for Alzheimer’s and Neurodegenerative Diseases and holds the Huffington Foundation Endowed Chair for Parkinson’s Disease Research at the Duncan NRI and the Effie Marie Cain Chair in Alzheimer’s Disease Research at Baylor.

Using a multidisciplinary approach that integrates human genomic analyses with functional investigation in experimental animal models of neurodegenerative disease, Dr. Shulman and his team have made several important discoveries that have led to a better understanding of the genes and mechanisms involved in Alzheimer’s and Parkinson’s diseases. In recognition of his stellar contributions to neurology, he received the prestigious 2020 Derek Denny-Brown Young Neurological Scholar Award from the American Neurological Association.

“The Duncan NRI truly is a special place, with an unparalleled collaborative and cross-disciplinary approach that propels groundbreaking research on brain diseases affecting children and adults alike,” said Dr. Shulman. “The success of my research program over the last decade owes much to the Duncan NRI and I am proud to serve as its Co-Director. It is a privilege to represent and support my outstanding colleagues at the Duncan NRI and to learn from and work with Dr. Huda Zoghbi to further Duncan NRI’s mission.”

###

About Texas Children’s Hospital

Texas Children’s Hospital, a not-for-profit health care organization, is committed to creating a healthier future for children and women throughout the global community by leading in patient care, education and research. Consistently ranked as the best children’s hospital in Texas, and among the top in the nation, Texas Children’s has garnered widespread recognition for its expertise and breakthroughs in pediatric and women’s health. The hospital includes the Jan and Dan Duncan Neurological Research Institute; the Feigin Tower for Pediatric Research; Texas Children’s Pavilion for Women, a comprehensive obstetrics/gynecology facility focusing on high-risk births; Texas Children’s Hospital West Campus, a community hospital in suburban West Houston; and Texas Children’s Hospital The Woodlands, the first hospital devoted to children’s care for communities north of Houston. The organization also created Texas Children’s Health Plan, the nation’s first HMO for children; Texas Children’s Pediatrics, the largest pediatric primary care network in the country; Texas Children’s Urgent Care clinics that specialize in after-hours care tailored specifically for children; and a global health program that’s channeling care to children and women all over the world. Texas Children’s Hospital is affiliated with Baylor College of Medicine. For more information, go to www.texaschildrens.org. Get the latest news by visiting the online newsroom and Twitter at twitter.com/texaschildrens.

About Baylor College of Medicine

Baylor College of Medicine (www.bcm.edu) in Houston is recognized as a health sciences university and is known for excellence in education, research and patient care. It is ranked 22nd among medical schools for research and 17th for primary care by U.S. News & World Report. Baylor is listed 20th among all U.S. medical schools for National Institutes of Health funding and No. 1 in Texas. The Baylor pediatrics program ranked 7th among all pediatric programs, reflecting the strong affiliation with Texas Children’s Hospital where our faculty care for pediatric patients and our students and residents train. Nationally our physician assistant program was ranked 3rd in the health disciplines category and our nurse anesthesia program ranked 2nd. Located in the Texas Medical Center, Baylor has affiliations with seven teaching hospitals and jointly owns and operates Baylor St. Luke’s Medical Center, part of St. Luke’s Health. Currently, Baylor has more than 3,000 trainees in medical, graduate, nurse anesthesia, physician assistant, orthotics and genetic counseling as well as residents and postdoctoral fellows. Follow Baylor College of Medicine on Facebook (http://www.facebook.com/BaylorCollegeOfMedicine) and Twitter (http://twitter.com/BCMHouston).

The reaction of narwhals to the loud noise from seismic air guns used in oil exploration involves a disruption of the normal physiological response to intense exercise as the animals try to escape the noise. The overall effect is a large increase in the energetic cost of diving while a paradoxically reduced heart rate alters the circulation of blood and oxygen.

“They’re swimming as hard as they can to get away, and yet their heart rate is not increasing—we think because of a fear response. This affects how much blood and oxygen can circulate, and that’s going to be problematic,” said Terrie Williams, a professor of ecology and evolutionary biology at UC Santa Cruz who led the new study.

Published July 8 in the Journal of Functional Ecology, the study provides the first look at the impact of seismic noise on the physiological responses of a deep-diving cetacean. According to Williams, the combination of extremely low heart rates, increased heart rate variability, and high-intensity exercise during deep dives presents a significant physiological challenge for narwhals, especially if the disruptions are prolonged as would be likely during extended oil exploration activities.

Narwhals live year-round in high Arctic waters where sea ice has helped isolate them from disturbance by humans for millions of years. But declines in polar sea ice are making the region more accessible to shipping, natural resource exploration, and other human activities.

In a previous study, Williams and her coauthors showed that narwhals released after entanglement in nets set by indigenous hunters showed a similar physiological response, with extremely low heart rates during intense exercise in a series of escape dives. The difference between a capture event and noise, Williams said, is the potential duration of the disturbance.

“When they escape from the nets, their heart rate comes back up to a more normal rate within three or four dives, but with the seismic ship moving through and the sound bouncing around, the escape response occurred over a longer period,” she said.

The researchers recorded not only extremely low heart rates during noise exposure, but also increased variability, with heart rates switching rapidly between extremely low rates associated with fear and fast rates associated with intense exercise. Reduced heart rate, or bradycardia, is a normal part of the mammalian dive response, but during normal dives the heart rate still increases with exercise. In addition, narwhals and other deep-diving marine mammals usually save energy by gliding rather than actively swimming as they descend to depth.

During noise exposure, the narwhals performed 80% less gliding during diving descents, their swimming strokes exceeded 40 strokes per minute, their heart rates dropped below 10 beats per minute, and their breathing at the surface was 1.5 times faster. Overall, this unusual reaction is very costly in terms of energy consumption, Williams said.

“Not only is the reaction costly in terms of the energy needed for diving, the escape time will also take away from time spent foraging for food and other normal behaviors,” she said.

The studies were conducted in Scoresby Sound on the east coast of Greenland, where coauthor Mads Peter Heide-Jørgensen, a research professor at the Greenland Institute of Natural Resources, has been studying the East Greenland narwhal population for more than a decade.

Williams’s group at UC Santa Cruz developed instruments that enable researchers to monitor the exercise physiology of marine mammals during dives. The instruments were attached to narwhals with suction cups and fell off after one to three days, floating to the surface where they could be recovered by the scientists.

Over the past two decades, noise from human activities such as military sonar has been linked to mass strandings of deep-diving cetaceans, mostly beaked whales. These deep-diving species are extremely difficult to study, and it was only through a partnership with indigenous hunters that Williams and Heide-Jørgensen’s teams were able to attach monitoring devices to narwhals.

“Most of the potential impacts on the animals take place underwater, so it’s really difficult to study,” Williams said. “We are fortunate to have this technology to show what’s happening at depth where these animals live in order to understand how their biology may be disrupted.”

In addition to Williams and Heide-Jørgensen, the coauthors of the paper include Susan Blackwell at Greeneridge Sciences, Outi Tervo and Eva Garde at the Greenland Institute of Natural Resources, Mikkel-Holger Sinding at University of Copenhagen, and Beau Richter at UC Santa Cruz. This work was supported by the U.S. Office of Naval Research, Greenland Institute of Natural Resources, the Environmental Agency for Mineral Resource Activities of the Government of Greenland, the Danish Ministry of Environment, and the Carlsberg Foundation.