Summary We are proposing a competitive revision for R01 HL163085, that will address in vitro and ex vivo the contribution of systemic vs pulmonary circulation conditions on the mechanisms of structural degeneration of implanted biomaterials for left and right side cardiac reconstruction approaches. Congenital heart defects (CHDs) affect nearly 1% of?or about 40,000?births per year in the United States. More than 40% of CHD patients require the replacement of one of the valves. Congenital lesions of any of the heart valves are associated with a wide spectrum of cardiac malformations, impacting both the left and right side of the heart. Left-side anomalies may involve any component of the Aortic or Mitral valve apparatus that result in stenosis, regurgitation, or mixed hemodynamic disturbances. In adulthood, common diseases of the mitral valve include degenerative mitral regurgitation (DMR) and ischemic mitral regurgitation (IMR), for the Aortic Valve, Aortic Insufficiency (AI), or stenosis. Several CHD primarily affect the right heart including Tetralogy of Fallot, transposition of great arteries, septal defects leading to pulmonary vascular disease, Ebstein anomaly and arrhythmogenic right ventricular cardiomyopathy. For both Left and Right sided CHD reconstructive surgeries, the biomaterials have several important limitations, impacting long-term biocompatibility and durability. The primary goals of the parent award HL 163085 are: to understand the mechanisms of accelerated structural degeneration of implantable biomaterials in pediatric and young adults by assessing the role of protein absorption on implanted biomaterials and to test mitigation strategies to extend the lifespan of these biomaterials in vitro, ex vivo, and in vivo by using juvenile and adult rat models. In this revised supplement we address how systemic vs pulmonary circulation conditions (including the different blood biochemistry and hemodynamic conditions) is impacting the materials used for reconstructive heart surgery.