Flexible drug-delivery patch can promote tissue healing after a heart attack

MIT engineers have developed a flexible drug-delivery patch that can be placed on the heart after a heart attack to help promote healing and regeneration of cardiac tissue.

The new patch is designed to carry several different drugs that can be released at different times, on a pre-programmed schedule. In a study of rats, the researchers showed that this treatment reduced the amount of damaged heart tissue by 50 percent and significantly improved cardiac function.

If approved for use in humans, this type of patch could help heart attack victims recover more of their cardiac function than is now possible, the researchers say.

When someone suffers a major heart attack, the damaged cardiac tissue doesn't regenerate effectively, leading to a permanent loss of heart function. The tissue that was damaged doesn't recover. Our goal is to restore that function and help people regain a stronger, more resilient heart after a myocardial infarction."

Ana Jaklenec, principal investigator at MIT's Koch Institute for Integrative Cancer Research

Jaklenec and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, are the senior authors of the new study, which appears today in Cell Biomaterials. Former MIT postdoc Erika Wang is the lead author of the paper.

Programmed drug delivery

After a heart attack, many patients end up having bypass surgery, which improves blood flow to the heart but doesn't repair the cardiac tissue that was damaged. In the new study, the MIT team wanted to create a patch that could be applied to the heart at the same time that the surgery is performed.

This patch, they hoped, could deliver drugs over an extended time period to promote tissue healing. Many diseases, including heart conditions, require phase-specific treatment, but most systems release drugs all at once. Timed delivery better synchronizes therapy with recovery.

"We wanted to see if it's possible to deliver a precisely orchestrated therapeutic intervention to help heal the heart, right at the site of damage, while the surgeon is already performing open-heart surgery," Jaklenec says.

To achieve this, the researchers set out to adapt drug-delivery microparticles they had previously developed, which consist of capsules similar to tiny coffee cups with lids. These capsules are made from a polymer called PLGA and can be sealed with a drug inside.

By changing the molecular weight of the polymers used to form the lids, the researchers can control how quickly they degrade, which enables them to program the particles to release their contents at specific times. For this application, the researchers designed particles that break down during days 1-3, days 7-9, and days 12-14 after implantation.

This allowed them to devise a regimen of three drugs that promote heart healing in different ways. The first set of particles release neuregulin-1, a growth factor that helps to prevent cell death. At the next time point, particles release VEGF, a growth factor that promotes formation of blood vessels surrounding the heart. The last batch of particles releases a small molecule drug called GW788388, which inhibits the formation of scar tissue that can occur following a heart attack.

"When tissue regenerates, it follows a carefully timed series of steps," Jaklenec says. "Dr. Wang created a system that delivers key components at just the right time, in the sequence that the body naturally uses to heal."

The researchers embedded rows of these particles into thin sheets of a tough but flexible hydrogel, similar to a contact lens. This hydrogel is made from alginate and PEGDA, two biocompatible polymers that eventually break down in the body. For this study, the researchers created compact, miniature patches only a few millimeters across.

"We encapsulate arrays of these particles in a hydrogel patch, and then we can surgically implant this patch into the heart. In this way, we're really programming the treatment into this material," Wang says.

Better heart function

Once they created these patches, the researchers tested them on spheres of heart tissue that included cardiomyocytes generated from induced pluripotent stem cells. These spheres also included endothelial cells and human ventricular cardiac fibroblasts, which are also important components of the heart.

The researchers exposed those spheres to low-oxygen conditions, mimicking the effects of a heart attack, then placed the patches over them. They found that the patches promoted blood vessel growth, helped more cells to survive, and reduced the amount of fibrosis that developed.

In tests in a rat model of heart attack, the researchers also saw significant improvements following treatment with the patch. Compared to no treatment or IV injection of the same drugs, animals treated with the patch showed 33 percent higher survival rates, a 50 percent reduction in the amount of damaged tissue, and significantly increased cardiac output.

The researchers showed that the patches would eventually dissolve over time, becoming a very thin layer over the course of a year without disrupting the heart's mechanical function.

"This is an important way to combine drug delivery and biomaterials to potentially new treatments for patients," Langer says.

Of the drugs tested in this study, neuregulin-1 and VEGF have been tested in clinical trials to treat heart conditions, but GW788388 has only been explored in animal models. The researchers now hope to test their patches in additional animal models in hopes of running a clinical trial in the future.

The current version of the patch needs to be implanted surgically, but the researchers are exploring the possibility of incorporating these microparticles into stents that could be inserted into arteries to deliver drugs on a programmed schedule.

Other authors of the paper include Elizabeth Calle, Binbin Ying, Behnaz Eshaghi, Linzixuan Zhang, Xin Yang, Stacey Qiaohui Lin, Jooli Han, Alanna Backx, Yuting Huang, Sevinj Mursalova, Chuhan Joyce Qi, and Yi Liu.

The researchers were supported by the Natural Sciences and Engineering Research Council of Canada and the U.S. National Heart, Lung, and Blood Institute.