Application of Bioadhesive to Heart Improves Survival in Preclinical Model of Myocardial Infarction

Even state-of-the-art treatments for acute myocardial infarction (MI) are limited in their ability to prevent cell injury, cell death and associated inflammation. Myocardial fibrosis and the adverse left ventricular remodeling it produces are responsible for the most common sequelae of MI, including impaired pump function, heart failure and ventricular arrhythmias.

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Direct application of hydrogels to the heart is being studied as a way to mechanically support weakened tissue, reduce scar formation and preserve left ventricular function. Hydrogels are polymer networks that absorb large amounts of water to sustain cellular growth.

Naturally occurring hydrogels are biocompatible with the heart and elastic enough not to interfere with normal muscle contraction. However, some previously tried materials have not adhered well to internal organs. To compensate, research groups have applied hydrogels in a liquid precursor form, then polymerized (hardened) them through exposure to gamma rays or ultraviolet light. However, the long-term safety of that exposure is unknown.

Leon M. Ptaszek, MD, PhD, a cardiac electrophysiologist at the Corrigan Minehan Heart Center at Massachusetts General Hospital and assistant professor of Medicine at Harvard Medical School, Jeremy Ruskin, MD, founder and director emeritus of the Telemachus & Irene Demoulas Family Foundation Center for Cardiac Arrhythmias at the Corrigan Minehan Heart Center at Mass General and professor of Medicine at Harvard Medical School, and Nasim Annabi, PhD, assistant professor of Chemical and Biomolecular Engineering at UCLA, and colleagues are investigating a hydrogel that can be polymerized with visible-spectrum light. They describe encouraging results from a proof-of-concept study in the Journal of the American Heart Association.

In Vitro Data

The researchers modified gelatin to form photo-cross-linkable gelatin methacryloyl (GelMA). The material proved to be adhesive, non-toxic, biodegradable and biocompatible with cardiomyocytes and fibroblasts.

GelMA was rapidly and efficiently polymerized. It was possible to "tune" the concentration of GelMA precursors and the duration of polymerization to match the elasticity of rat myocardium. GelMA maintained structural integrity for at least 14 days.

Animal Model of MI

Immediately after generating MI in mice, the researchers placed the liquid bioadhesive precursor directly on the hearts of 20 mice, then exposed it to visible light. Twenty control mice received no treatment.

GelMA adhered strongly and was safe. It was associated with significantly lower mortality during a three-week observation period after MI.

Postmortem inspection of mice that did not survive revealed LV rupture as the cause of death. Thus, GelMA treatment probably reduced mortality by preventing LV rupture.

GelMA-treated mice that survived the three-week monitoring period exhibited improved LV systolic function and reduced scar burden compared with untreated mice. The reduced scar burden suggests that GelMA functions as a biomimetic scaffold on the heart.

Clinical Applications

It's hoped that in humans, GelMA will eventually be administered percutaneously using a map-guided system for catheter-based transmyocardial injection. Another goal is for GelMA to provide a platform for sustained release delivery of drug or cell therapies during an approximate three-week post-MI healing period.

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