Could carbon monoxide foam help fight inflammation?

image: Foam Gas Entrapment Materials (GEM)
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Credit: Courtesy of the researchers

CAMBRIDGE, MA — Carbon monoxide is best known as a potentially deadly gas. However, in small doses, it also has beneficial qualities: it has been shown to reduce inflammation and can help stimulate tissue regeneration.

A team of researchers led by MIT, Brigham and Women’s Hospital, University of Iowa and Beth Israel Deaconess Medical Center has now developed a new way to deliver carbon monoxide to the body while bypassing its effects potentially dangerous. Inspired by techniques used in molecular gastronomythey were able to incorporate carbon monoxide into stable foams that could be delivered through the digestive tract.

In a study on mice, researchers showed that these foams reduced colon inflammation and helped reverse acute liver failure caused by an overdose of acetaminophen. The new technique, described today in a Science Translational Medicine paper, could also be used to deliver other therapeutic gases, according to the researchers.

“The ability to deliver a gas opens up whole new opportunities for how we think about therapeutics. We don’t typically think of a gas as a medicine that you would take orally (or could be given rectally), so this offers an exciting new way of thinking about how we can help patients,” says Giovanni Traverso. , the Karl van Tassel Career Development Assistant Professor of Mechanical Engineering at MIT and gastroenterologist at Brigham and Women’s Hospital.

Traverso and Leo Otterbein, professor of surgery at Harvard Medical School and Beth Israel Deaconess Medical Center, are the lead authors of the paper. The lead authors are James Byrne, physician-scientist and radiation oncologist at the University of Iowa (formerly a resident of the Mass General Brigham/Dana Farber Radiation Oncology Program), and a researcher affiliated with the Koch Institute for Integrative Cancer Research at MIT; David Gallo, researcher at Beth Israel Deaconess; and Hannah Boyce, research engineer at Brigham and Women’s.

Delivery by foam

Since the late 1990s, Otterbein has been studying the therapeutic effects of low doses of carbon monoxide. The gas has been shown to confer beneficial effects in preventing rejection of transplanted organs, reducing tumor growth, and modulating inflammation and acute tissue damage.

When inhaled in high concentrations, carbon monoxide binds to hemoglobin in the blood and prevents the body from getting enough oxygen, which can lead to serious health effects and even death. However, at lower doses, it has beneficial effects such as reducing inflammation and promoting tissue regeneration, says Otterbein.

“We have known for years that carbon monoxide can have beneficial effects on all kinds of pathologies, when administered as an inhaled gas,” he says. “However, its use in the clinic has been a challenge, for a number of reasons related to safe and reproducible administration, and healthcare worker concerns, leading people to want to find other ways to ‘administer.”

A few years ago, Traverso and Otterbein were introduced by Christoph Steiger, a former MIT postdoc and author of the new study. Traverso’s lab specializes in the development of new methods of drug delivery to the gastrointestinal tract. To meet the challenge of providing a gas, they came up with the idea of ​​incorporating the gas into a mousse, much like chefs use carbon dioxide to create mousses infused with fruits, vegetables, or other flavors.

Culinary foams are typically created by adding a thickening or gelling agent to a liquid or solid that has been pureed, then whisking it to incorporate air or by using a specialized siphon that injects gases such as dioxide carbon or compressed air.

The MIT team created a modified siphon that could be attached to any type of gas canister, allowing them to incorporate carbon monoxide into their foam. To create the foams, they used food additives such as alginate, methylcellulose and maltodextrin. Xanthan gum has also been added to stabilize the foams. By varying the amount of xanthan gum, the researchers were able to control the time it took for the gas to be released once the foams were administered.

After showing that they could control the timing of gas release in the body, the researchers decided to test the foams for a few different applications. First, they investigated two types of topical applications, analogous to applying a cream to soothe itchy or inflamed areas. In a study on mice, they found that giving the foam rectally reduced inflammation caused by colitis or radiation-induced proctitis (inflammation of the rectum that can be caused by radiation therapy for cervical cancer). uterus or prostate).

Current treatments for colitis and other inflammatory conditions such as Crohn’s disease typically involve drugs that suppress the immune system, which can make patients more susceptible to infections. According to the researchers, treating these conditions with a foam that can be applied directly to the inflamed tissue offers a potential alternative or complementary approach to these immunosuppressive treatments. Although the foams were administered rectally in this study, it might also be possible to administer them orally, according to the researchers.

“The foams are so easy to use, which will make it easier to translate to patient care,” says Byrne.

Control dose

Researchers then set out to investigate possible systemic applications, in which carbon monoxide could be delivered to distant organs, such as the liver, due to its ability to diffuse from the gastrointestinal tract elsewhere in the body. the body. For this study, they used a mouse model of acetaminophen overdose, which causes severe liver damage. They found that gas delivered to the lower gastrointestinal tract was able to reach the liver and significantly reduce the amount of inflammation and tissue damage seen there.

In these experiments, the researchers found no adverse effects after the administration of carbon monoxide. Previous studies in humans have shown that small amounts of carbon monoxide can be safely inhaled. A healthy individual has a carbon monoxide concentration of about 1% in the blood, and studies with human volunteers have shown that levels as high as 14% can be tolerated without adverse effects.

“We think that with the foam used in this study, we’re not even getting close to the levels that we would be concerned about,” Otterbein says. “What we’ve learned from the inhaled gas trials has paved the way for saying it’s safe, as long as you know and can control how much you give, much like any medicine. It’s a another interesting aspect of this approach: we can control the exact dose.

In this study, the researchers also created gels containing carbon monoxide, as well as gas-filled solids, using techniques similar to those used to make Pop Rocks, the hard candies that contain bubbles of carbon dioxide. under pressure. They plan to test them in further studies, in addition to developing the foams for possible testing in human patients.

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The research was supported, in part, by a Prostate Cancer Foundation Young Investigator Award, an Early Investigator Award from the Department of Defense Prostate Cancer Program, a Hope Funds Fellowship for Cancer Research, the National Football League Players Association, the Department of Defense and MIT. Department of Mechanical Engineering.


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