Background: Transcatheter aortic valve replacement (TAVR) is a minimally invasive alternative to surgical valve replacement, originally targeted to elderly patients with aortic stenosis (AS), now increasingly utilized in younger lower risk AS patients. With growth of TAVR the shortcomings of current tissue-based valves are becoming prevalent, namely limited durability and thromboembolic risk. To address these, a polymeric TAV named PolyV-2 (27 mm, PolyNova Cardiovascular Inc, Stony Brook, NY) was designed, optimized, and further tested. Methods: The design of the PolyV-2 (Figure A) was achieved with a battery of in silico simulations including the use of finite element analysis (FEA, Abaqus 2020, Dassault Systems, Providence, RI) to optimize the radial force of the stent frame and minimize leaflet stresses during the cardiac cycle. The PolyV-2 employs a sutureless design via coating the stent with polymer, bypassing problematic hand suturing manufacture of tissue valves. The PolyV-2 utilizes a thermoplastic elastomer polymeric material which was tested in vitro with accelerated wear durability testing according to ISO 5840-3 (2015) with periodic performance testing, evaluated against tissue-based surgical and TAV devices for platelet activation rate (PAR) in a pulsatile flow loop, and evaluated for calcification risk with similar wear testing in a pro-calcific medium. To assess the deposition of calcifications in the valves, both µCT and ICP spectroscopy were used. Results: The optimization process of the PolyV-2 leaflets (Figure B) was able to greatly lower the peak and mean stresses throughout over the cardiac cycle by employing a variable thickness across the entire leaflet. With success of this in silico optimization process, the leaflets were then tested in vitro (Figure C) in accelerated wear testing, performing 1Billion cycles w/o failure – correlating to 25 years of efficacy in vivo, exceeding the 250 million minimum required by the FDA. The material also demonstrated favorable hemocompatiblity as to PAR (Figure D) with activation significantly lower than a commercial tissue TAVR device, more comparable to a surgical device. The pro-calcific wear testing demonstrated no deposition of calcific salts within the polymer leaflet (µCT image, Figure E) compared to the tissue valve and minimal calcium detected with ICP spectroscopy. Conclusion: To mitigate the persistent complications of tissue-based TAV devices, the polymeric PolyV-2 valve was optimized through a battery of in silico and in vitro trials to offer superior hemodynamics, performance, and durability. Proper design and material considerations are essential to ensure successful translation, demonstration of enhanced bio/hemocompatibility and advance of the PolyV-2 through in vivo animal trials.