With an estimated 635,000 Americans with coronary artery disease (CAD) each year, there is a clear need for an alternative treatment strategy. Myocardial infarction (MI) is a leading CAD caused by the death of heart muscle tissues. The current treatment paradigm is focused on pharmacological (reducing oxygen demand or increasing blood flow) or surgical intervention including surgical bypass to reconstruct blood flow path. Recent work has taken a more biomedical approach in which angiogenesis using growth factors in infarction site is targeted as a means to provide blood flow and oxygen supply. While some approaches are dependent on direct administration of pure growth factors, experience in the wider field of cardiovascular tissue engineering has taught us that a scaffold-based approach may be the most promising strategy. We have recently developed a polymeric injectable biomaterial that serves itself well to this application owing to is reverse thermal gelling properties. These properties allow it too rapidly and reversibly transition between a liquid at room temperature and a solid at body temperature, permitting injection through a small gauge needle or catheter directly at the target site and then formation of a cohesive solid polymer network upon reaching body temperature. This approach has many advantages over other scaffold-based approaches including minimally- invasive deployment, in situ conformation to the injury site and tunable physical properties to mimic the host environment. In addition, this system can be readily functionalized to mimic specific biofunction of natural heparin to enhance stability and localized expression of growth factors, and thereby achieve localized angiogenesis in MI site with substantial recovery of heart function. Towards developing a system that can maximize these advantages, we have constructed this application around two specific aims: 1) determine appropriate version of heparin-mimicking reverse thermal gel (SRTG) that substantially sustains growth factor expression in vitro and 2) demonstrate substantial angiogenesis and MI treatment effect by in vivo rat MI model.

Public Health Relevance

Over past decades, the number of medical treatment options for patients with myocardial infarction, a leading ischemic cardiovascular disease, has steadily increased with new drugs being developed every few years. Despite this attention from the research and development community, the percentage of patients that receive proper medical treatment and still experience recurrent attack is significant. An alternative treatment strategy using injectable biomaterial with a capacity of localized expression of angiogenic agents has been developed in which the formation of new blood vessel in infarcted site is targeted with a purpose of regenerating blood flow, a passage of sufficient oxygen supply and nutrient to the infarcted site. This temperature-responsive injectable biomaterial addresses myocardial infarction in a one-time treatment platform that removes patient compliance as a barrier to therapeutic success. It is expected that this system will significantly improve heart function in patients with myocardial infarction as well as provide a platform for cardiovascular regeneration.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Lee, Albert
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University of Colorado Denver
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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Peña, Brisa; Laughter, Melissa; Jett, Susan et al. (2018) Injectable Hydrogels for Cardiac Tissue Engineering. Macromol Biosci 18:e1800079
Peña, Brisa; Bosi, Susanna; Aguado, Brian A et al. (2017) Injectable Carbon Nanotube-Functionalized Reverse Thermal Gel Promotes Cardiomyocytes Survival and Maturation. ACS Appl Mater Interfaces 9:31645-31656
Peña, Brisa; Shandas, Robin; Park, Daewon (2015) A heparin-mimicking reverse thermal gel for controlled delivery of positively charged proteins. J Biomed Mater Res A 103:2102-8