Milica Radisic

U of T researchers create ‘training gym’ for lab-grown heart cells

Christopher.Sorensen — Thu, 24 Jan 2019 19:02:32 +0000

U of T researchers create ‘training gym’ for lab-grown heart cells

Christopher.Sorensen Thu, 01/24/2019 - 14:02

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U of T researcher Yimu Zhao demonstrates the BioWire II, a platform for growing heart cells outside the body that could enhance drug development and personalized medicine (photo by Bill Dai)

Tyler Irving

Topic

Global Lens

Faculty of Applied Science & Engineering

Global

Graduate Students

Milica Radisic

Research & Innovation

Heart muscle cells need exercise – even when they grow outside the human body.

A new device designed by researchers at the �ؿ�ζSM's Faculty of Applied Science & Engineering uses a rigorous training regimen to grow small amounts of cardiac tissue and measure how strongly it beats.

The platform is ideal for testing the effects of potential drug molecules, and could help bring personalized medicine closer to reality.

“Many potential new drugs fail because of toxicity issues, and cardiac toxicity is a major challenge,” says Milica Radisic, a professor at the Institute of Biomaterials and Biomedical Engineering who led the research team.

“You can test potential drugs on heart cells grown in a petri dish, but those cells don’t look the same as the cells in a real heart, and you can’t get much information about their actual cardiac function.”

Radisic, who is cross-appointed to the department of chemical engineering and applied chemistry, and her research collaborators build devices that enable lab-grown cells and tissues to develop into 3D forms that more closely resemble those in the human body. Five years ago, they created the Biowire, a platform in which heart cells grow around a silk suture. By pulsing electricity through the cells, the device causes them to elongate and become more like mature human heart cells.

Their latest paper, published today in the journal Cell, describes a new platform dubbed Biowire II. It contains two wires made of elastic polymers positioned three millimetres apart, with heart cells forming a small band of tissue between them. Each time the cells contract, they bend the wires. By measuring the amount of deflection in the wires, the researchers can determine the force of the contraction.

“The advantage of this system is that it tells us how a given drug molecule is affecting the cardiac output by examining forces of contraction and other key functional readouts,” says Yimu Zhao, a PhD candidate in Radisic’s lab and the lead author on the paper.

“Does it weaken the heart or make it stronger? It will help find new drugs to treat heart conditions, but also eliminate drugs for other conditions that have adverse effects on the heart.”

As with the original Biowire, electrical pulses are used to simulate exercise and “train” the heart cells. Zhao says the team has refined the training regimen to create tissue that is even more life-like than what was possible with the previous device – all in just six weeks.

“We have created both atrial and ventricular heart tissues, and we can even grow a heteropolar tissue – one with both atrial and ventricular ends,” says Zhao.

“Some drugs have a selective action on one or the other. With this system, we can detect this more efficiently.”

Lab-grown heart tissue, suspended between two strands of elastic polymer, beats inside the Biowire II. The platform both incubates the cells and measures how strongly they are contracting in real time (image courtesy of Yimu Zhao)

Zhao says that one of the most impressive tests of the system came when the device was seeded with six different cell lines. Three came from patients with a condition called left ventricular hypertrophy, while the other three came from patients without the condition.

“It was a blind trial, nobody in our lab knew which cell line was which,” says Zhao. “But as they grew in the device, we could clearly identify the tissues from patients with the condition by loss of contractility, which is one of the hallmarks of the disease.

“When we confirmed the results with our collaborators, they were so surprised – we got it exactly right.”

The ability to accurately replicate the heart condition of a real patient opens the door to new applications in personalized medicine. In addition to studying the progression of disease in a particular patient, the model heart could also be used to screen several potential treatments simultaneously, narrowing in on the ones most likely to be effective.

More research will be required before the platform can be used in this way, but Biowire II is already finding commercial application through TARA Biosystems Inc., a spinoff co-founded by Radisic. The company uses its lab-grown heart tissues to carry out cardiac drug testing studies for pharmaceutical companies.

“We worked closely with them on this study,” says Zhao. “They are already using a modified version of our protocol.” She adds that the simplicity of the system will make it easier for companies like TARA to scale up the technology and increase the number of tests they can carry out simultaneously.

Ultimately, lab-grown tissues may one day be implanted back into humans to repair damaged organs. Radisic and her team are pursuing separate technologies to address that challenge, but she says the fact that Biowire II is already having an impact is gratifying.

“If our lab-grown tissues can keep dangerous drugs out of the pipeline and help find new drugs to treat heart conditions, it will save thousands of lives,” Radisic says.

The team's research was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada, among others.

U of T's Milica Radisic awarded 2017 Steacie Prize

noreen.rasbach — Mon, 18 Dec 2017 21:39:51 +0000

U of T's Milica Radisic awarded 2017 Steacie Prize

noreen.rasbach Mon, 12/18/2017 - 16:39

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Professor Milica Radisic holds the Canada Research Chair in Functional Cardiovascular Tissue Engineering (photo by Caz Zyvatkauskas)

Carolyn Farrell

Topic

Our Community

Faculty of Applied Science & Engineering

Milica Radisic

The �ؿ�ζSM's Milica Radisic has been named the 2017 recipient of the Steacie Prize, awarded each year to an engineer or scientist 40 years of age or younger who has made notable contributions to research in Canada.

The prize is administered by the E.W.R. Steacie Memorial Fund, a private foundation dedicated to the advancement of Canadian science and engineering.

As the Canada Research Chair in Functional Cardiovascular Tissue Engineering, Radisic of the Faculty of Applied Science & Engineering has made transformational advances in tissue engineering resulting in new methods for growing human tissue in the lab. Radisic was the first in the world to use electrical impulses and specially designed bioreactors to guide isolated heart cells to assemble into a beating structure. These beating heart tissues are already being used to test potential drugs for side-effects.

Radisic and her team recently developed an injectable tissue patch that could help repair hearts, livers or other organs damaged by disease or injury, potentially eliminating the need for invasive transplant surgeries. They have also created the AngioChip, a 3D, fully vascularized piece of heart tissue that beats in real time. Radisic’s technologies are the foundation for the startup TARA Biosystems, which is now working with several major pharmaceutical companies on drug discovery and validation using the matured human heart tissues developed in her lab.

U of T researchers make skin cells ‘crawl’ together to heal wounds treated with unique hydrogel layer

geoff.vendeville — Thu, 15 Dec 2016 16:22:17 +0000

U of T researchers make skin cells ‘crawl’ together to heal wounds treated with unique hydrogel layer

geoff.vendeville Thu, 12/15/2016 - 11:22

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Researchers Lewis Reis (left) and Milica Radisic (right) work on their unique peptide-hydrogel biomaterial, which heals chronic wounds up twice as quickly as commercially available products (photo by Marit Mitchell)

Marit Mitchell

Author legacy

Marit Mitchell

Topic

Breaking Research

Regenerative Medicine

Faculty of Applied Science & Engineering

Milica Radisic

IBBME

Subheadline

Research team led by Engineering Professor Milica Radisic uses its patented peptide to close non-healing chronic wounds caused by diabetes

Time may not heal all wounds, but a proprietary mix of peptides and gel developed by U of T researchers heals most.

A team led by Faculty of Applied Science & Engineering Professor Milica Radisic has demonstrated for the first time that a peptide-hydrogel biomaterial prompts skin cells to “crawl” toward one another, closing chronic, non-healing wounds often associated with diabetes such as bed sores and foot ulcers.

The team tested their biomaterial on healthy cells from the surface of human skin called keratinocytes as well as on keratinocytes derived from elderly diabetic patients. They saw non-healing wounds close 200 per cent faster than with no treatment and 60 per cent faster than treatment with a leading commercially used collagen-based product.

“We were happy when we saw the cells crawl together much faster with our biomatieral, but if it didn’t work with diabetic cells, that would have been the end of the story,” says Radisic. “But even the diabetic cells travelled much faster – that’s huge.”

Until now, most treatments for chronic wounds involved applying topical ointments that promote the growth of blood vessels to the area. But in diabetic patients, blood vessel growth is inhibited, making those treatments ineffective. Radisic and her team have been working with their special peptide – called QHREDGS or Q-peptide for short – for almost 10 years. They knew it promoted survival of many different cell types, including stem cells, heart cells and fibroblasts (the cells that make connective tissues) but had never applied it to wound healing.

“We thought that if we were able to use our peptide to both promote survival and give these skin cells a substrate so they could crawl together, they would be able to close the wound more quickly,” says Radisic. “That was the underlying hypothesis.”

At left, skin cells without the research team’s peptide-hydrogel treatment. In the middle, cells treated with a low dose. At right, cells treated with a high dose. Skin cells migrate together fastest with a high dose of the peptide-hydrogel material (photo courtesy of Radisic Lab)

Radisic and PhD students Yun Xiao and Lewis Reis compared the Q-peptide-hydrogel mix to the commercially available collagen dressing, to hydrogels without the peptide and to no treatment. They found that a single dose of their peptide-hydrogel biomaterial closed the wounds in less than two weeks. Their work was published in the journal Proceedings of the National Academy of Sciences.

“Currently, there are therapies for diabetic foot ulcers, but they can be improved,” says Xiao, the paper’s lead author. “Diabetic wound healing is a complicated condition, because many aspects of the normal wound healing process are disrupted – I know people with diabetic foot ulcers, and the possibility to improve their lives drove me throughout this work.”

The multidisciplinary team worked with Covalon Technologies Ltd., a company dedicated to the research and development and commercialization of novel health-care technologies, on this project. Covalon’s chief scientific officer, Val DiTizio, has been leading the partnership with Radisic’s group for about three years, and contributed its collagen-based wound-healing dressing, ColActive, as one of the controls.

“We believe strongly in keeping abreast of new technologies being developed in academia,” says DiTizio, who is also working with Radisic on a bone-regeneration project. “Collaborations such as this one inform our future research directions and help make our products better.”

This finding could have big implications for many types of wound treatments, from recovery after a heart attack to healing post-surgery. Accelerated healing times also introduces the added benefit of reducing the opportunity for infection, says Reis.

“One of the biggest challenges with the work was convincing our peers that the results we were getting were indeed true as they were staggering, even to us,” he says. “Being confident in our methods and diligent in our research and analysis prevailed in the end.”

Milica Radisic

U of T researchers create ‘training gym’ for lab-grown heart cells

U of T's Milica Radisic awarded 2017 Steacie Prize

Read more about Milica Radisic's research

U of T researchers make skin cells ‘crawl’ together to heal wounds treated with unique hydrogel layer