PHILADELPHIA — Combating the tissue degrading enzymes that cause lasting damage following a heart attack is tricky. Each patient responds to a heart attack differently and damage can vary from one part of the heart muscle to another, but existing treatments can’t be fine-tuned to deal with this variation.
A team of researchers from the University of Pennsylvania have developed a way to address this problem via a material that can be applied directly to the damaged heart tissue. The potentially dangerous enzymes break down this gel-like material, releasing enzyme inhibitors contained within. This responsive, balancing approach is ideal for keeping enzymes at the right level to minimize the long-term damage that can lead to congestive heart failure.
The ability of this gel to deliver enzyme inhibitors as needed suggests that the researchers’ technique might also find use in other inflammation-related disorders, such as osteoarthritis where the same enzymes degrade cartilage tissue.
A study demonstrating their design’s efficacy in an animal model was published in the journal Nature Materials. It was led by Jason Burdick, PhD, professor of bioengineering in Penn’s School of Engineering and Applied Science, and Brendan Purcell, PhD, a post-doctoral researcher in his lab. Joseph Gorman, MD, and Robert Gorman, MD, of the Department of Surgery in Penn’s Perelman School of Medicine contributed to the research.
The study is part of an ongoing collaborative research effort between the Gorman Cardiovascular Research Group and the Burdick Biomaterials Laboratory, developing therapies intended to improve the heart’s long-term response to a heart attack.
“While most groups working in this field are attempting to develop myocardial regenerative therapies, our team is focused on the biomechanical stabilization of the heart after heart attack,” Robert Gorman, MD, said. “Most researchers working towards regenerative therapies often overlook an important fact, namely, that the overwhelming majority of patients who suffer heart attack initially have adequate heart function. We strongly believe that optimizing the function of the surviving heart muscle after heart attack will be a more realistic and effective strategy than trying to regenerate the muscle that is lost.”
“What’s appealing about our approach,” Dr. Burdick said, “is that we are trying to intervene early. We want to attenuate the remodeling process to limit these negative outcomes and prevent the onset of congestive heart failure.”
Remodeling is a phenomenon that ultimately changes the overall shape and performance of the heart. After a heart attack, the body naturally releases enzymes as part of the inflammatory response to injury. But when this response is sustained too long, those enzymes begin to break up the extracellular matrix inside the muscle tissue that makes up the walls of the heart, making it thinner and weaker. The walls balloon out under the pressure of normal heart pumping, resulting in an enlarged heart that pumps less blood with each beat.
Synthetic or lab-grown versions of inhibitors to the tissue-degrading enzymes have been used in clinical trials, but only in a non-targeted fashion. Patients receive them intravenously or orally, with the hope that the inhibitor molecules make their way to the heart.
The material the researchers used in the study is known as a hydrogel, which in this design are squishy networks of sugars that are useful in mimicking different tissue environments. By making the hydrogel out of naturally occurring sugars, the researchers were able to hold the inhibitors within the hydrogel. They are hopeful that their results in an animal model will pave the way toward clinical use in human patients, where the gel would be applied to hearts via a catheter after the acute danger of a heart attack has passed.
The research was supported by National Institutes of Health and a Veterans’ Affairs Health Administration Merit Award. Dr. Jason Burdick, Dr. Joseph Gorman and Dr. Robert Gorman are each faculty members at the University of Pennsylvania ("Penn") and are the inventors of patent applications owned by Penn that describe the compositions of a biocompatible hydrogels capable of releasing inhibitors in response to the activity level of proteases. The inventors are currently working with Penn's Center for Technology Transfer to develop this technology for specific commercial product applications.
For more information, see the full news release on the University of Pennsylvania’s website.
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