Hydrogel can heal a broken heart

Bioengineers from the University of California, San Diego have found that an injectable hydrogel can repair the damage caused by heart attacks. Using a pig model, the researchers showed that the gel helped the heart grow new tissue and blood vessels while reducing scar tissue. Their study has been published in Science Translational Medicine.

During myocardial infarction (MI), or a heart attack, a blockage in the coronary artery causes cell death, degradation of the associated extracellular matrix (ECM) and an inflammatory response. A tough scar forms over the heart to help it heal but cannot contribute to its pumping, resulting in a weakening of the underlying tissue and, ultimately, heart failure (HF).

There are methods in place to prevent the process of negative left ventricular (LV) remodelling, but the UCSD researchers found these to be either unsuccessful or too invasive. They turned to using ECM-based materials as a biomaterial scaffold, with the aim of injecting it into the heart through a catheter in a minimally invasive procedure. Karen Christman, leader of the study, said that her team used ECM derived from a porcine heart, from the left ventricle - ie, the area they’re trying to treat.

“We strip out all the cells and just isolate the extracellular matrix, which is a protein framework that all of your cells sit in,” Christman said in a Science Translational Medicine podcast. “The idea of using that was that once you have a heart attack, your natural extracellular matrix is degraded in your heart, and the cells no longer have anything to attach to or help to grow new tissues. So we thought the best thing to deliver to the heart would be what was initially there in the first place.”

As explained by Jean Wang, a PhD student in the Christman lab, the ECM is turned into a gel by being chopped up and placed in a detergent mixture to remove all the cellular contents, leaving only the structural proteins that make up a tissue. That is freeze-dried into a Styrofoam-like substance, before being milled into a fine powder and liquefied using an enzyme.

 

Tissue spins in a beaker at the end of the cleansing process that removes all of the cells. The process retains the tissue’s structural proteins, a key component of the hydrogel. (UC San Diego Jacobs School of Engineering)

When the liquid is injected into the damaged heart tissue, it forms a gel. Once this occurs, says Christman, the ECM “can reassemble back into that natural scaffold”, providing a structural framework to encourage stem cells and new blood vessels to migrate into the damaged tissue. After completing its repair job, the hydrogel is degraded by the body.

The researchers had previously tested this gel in rats, proving that the material did in fact reassemble and help with cardiac function over a short timeframe. The next step was testing it in a larger animal - in this case, pigs - over a longer period.

Two weeks after triggering blood clots in the test pigs, resulting in MI, they were injected with the hydrogel material via a catheter inserted into an artery and directed through the blood vessels into the left ventricle. Over three months, various parameters were compared between the test animals and controls. These included:

• Ejection fraction (EF) - the fraction of blood pumped out of the ventricle with each heartbeat.
• LV end-diastolic volume (EDV) - the volume of blood remaining in the ventricle at end load or filling in.
• End-systolic volume (ESV) - the volume of blood in a ventricle at the end of contraction and the beginning of filling.

At the end of the three months, the EF of the matrix group was, according to the researchers, “significantly greater and their EDV and ESV were significantly smaller than those of the control animals”.

“EDV was decreased in 50% of the matrix-injected animals, whereas it increased in 75% of the control animals … the ESV improved with myocardial matrix injection in four of six animals, whereas every control animal had increased ESV,” they said.

After the three months, the animals were euthanised and their organs were studied. All matrix-injected hearts had a band of muscle along the endocardium, whereas the non-injected control animals had an endocardium that appeared as a thin layer with endothelium, with a loose fibrillar layer beneath this.

Microscopic images of pig hearts damaged by heart attack show the growth of new heart muscle tissue (shown in red, Figure A) after treatment with the injectable hydrogel compared to a heart left untreated (Figure B). (Karen Christman, UC San Diego Jacobs School of Engineering)

The researchers noted that such an effect has been observed in other studies through the injection of materials such as peptide nanofibres - however, they had to be co-delivered with a growth factor and did not improve EF.

“Here,” the researchers said, “the material alone increased cardiac muscle and improved contractility.”

Further experiments were conducted in rats to assess safety and biocompatibility. Healthy rats received doses of either decellularised porcine myocardial matrix (PMM) or non-decellularised porcine myocardial matrix (NDM). Evaluation showed that adverse side effects such as inflammation and lesions only occurred in the latter group, showing that the matrix is safe when the cellular content has been properly removed.

Christman added that since there is always some leakage when dealing with catheters going inside the heart, it is important that the material is compatible with human blood. A number of tests were conducted both in vivo and in vitro to ensure the gel had no effect on the blood’s clotting. There was no change in clotting times with the addition of the material and no platelet activation with the addition of the standard material concentration.

Having now confirmed the success of the gel in both small and large animals, the researchers believe it is ready to be tested in clinical trials. Start-up company Ventrix, co-founded by Christman, is currently finalising the manufacture of a clinical-grade product. Christman said the company hopes to conduct a clinical trial in Europe later this year.

Christman has high hopes for the gel, believing it has the potential to treat HF patients and reverse some of their decline in cardiac function. But initially, the team is targeting patients with depressed cardiac function after MI, in order to prevent them from going into HF in the first place.