Engineering an aortic valve with cellular and mechanical functionality

Heart valve disease is an increasing clinical burden associated with high morbidity and mortality. Current, valve replacements have a number of risks, such as thrombogenicity and calcification. For pediatric patients, a significant issue is the lack of small implants capable of growing, resulting in several surgical interventions for valve refitting. Patient-specific, tissue engineered heart valves (TEHVs) have the potential to address these issues through their self-repairing and remodeling capacity. The overall objective of this thesis was to develop a TEHV that functions under physiological aortic valve conditions and has the potential to repair and remodel over time. The central hypothesis is a TEHV can be created by mimicking the structural components of the valve leaflet layers using 3D bioprinting and incorporating valvular interstitial cell (VIC)-like cells to actively regenerate and remodel. First, we generated a potential suitable cell source of human iPSC-derived mesenchymal stem cells (iMSCs) that mature into VIC-like cells. Next, we used 3D printing and a combination of poly-ε-caprolactone (PCL) and gelatin methacrylate - polyethylene (glycol) diacrylate (GelMA/PEGDA) hydrogel to create a cell-laden multilayered leaflet that recapitulates the layers of the valve leaflet. Lastly, the PCL-component of the valve leaflet was mounted onto a valve stent and feasibility studies were conducted using a left-ventricle flow simulator to evaluate the hemodynamic performance of the PCL-TEHV under aortic valve conditions. We demonstrated a cell source can be derived from autologous iPSCs, generated a multilayered leaflet scaffold using a combination of natural and synthetic biomaterials, and verified the feasibility of the leaflet under aortic flow conditions. These promising findings are the first steps to a pre-clinical TEHV with the ability to regenerate and remodel with the patient.Ph.D