Perspective on the development of a bioengineered patch to treat heart failure: rationale and proposed design of phase I clinical trial

Abstract

This perspective focuses on the development of tissue engineered (TE) cell-based therapies to treat left ventricular (LV) dysfunction and chronic heart failure (CHF). The development of induced pluripotent stem cells enabled investigators to seed or co-culture human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) alone and in combination with other cells onto bioengineered scaffolds applied to the epicardial surface of the damaged left ventricle. Using our work as an example, we show how a xenograft implant of a bioengineered scaffold embedded with human neonatal fibroblasts and seeded with hiPSC-CMs partially reversed maladaptive LV remodeling and improved LV systolic/diastolic function in an immune-competent rat model of CHF. The fibroblasts lay down an extracellular matrix and secrete growth factors that increase myocardial blood flow. This approach provides an improved cell payload that covers a larger area of the damaged left ventricle as opposed to direct cell injections into the heart or down the coronary arteries. These studies combined with ongoing studies in immune-competent Yucatan mini swine treated with the same xenograft led to the preliminary design of a proposed Phase I clinical trial that will be presented to the Federal Drug Administration. For the proposed Phase I clinical, this TE patch will be implanted onto the epicardial surface of non-immunosuppressed patients undergoing elective Coronary Artery Bypass Grafting with Ejection Fractions ≥ 20% and ≤ 45%. The primary endpoints will be adverse events/severe adverse events associated with placing the TE patch on the heart. While Phase I trials are primarily safety trials, this proposed trial is designed to obtain some potential efficacy endpoints to help with the design of future Phase II/III clinical trials. These endpoints include changes in LV remodeling that were seen in the pre-clinical animal models as well as including endpoints that focus on patient well-being.