Polymeric valves appearing on the transcatheter horizon

Transcatheter pulmonary-valve replacement (TPVR) has emerged as a valid alternative for the treatment of congenital pulmonary-valve and right-ventricular outflow-tract (RVOT) malformations [1]. The primary goal of TPVR is to reduce the number of repoerations albeit at the cost of additional re-interventions throughout lifetime. This results from the young age at the index procedure and the high rate of long-term structural valve failure of the implanted bioprostheses [1]. The currently used xenogenic bioprostheses for TPVR are prone to continuous degeneration and calcificationsimiliar to what is seen in surgical valves. The course of structural valve failure is often accelerated in the young [2]. Polymeric valves have been suggested as a promising alternative to overcome such limitations due to their proposed superior durability over mechanical valves and their enhanced haemodynamic-profile over bioprostheses [3]. Lutter et al. [4] present a novel polymeric tri-leaflet heart valve made from polycarbonate urethane using a dip-coating technique and mounted onto a novel conical-shaped self-expanding nitinol stent. A TPVR procedure was performed in 6 sheep with an up to 6 months follow-up. All valves but 1 showed a good in vivo performance, a sufficient leaflet behaviour and an unchanged peak-to-peak gradient (4–5 mmHg) over time. A good stent integration and adjacent tissue ingrowth was observed while no stent fractures or thrombus formation was seen. No uncontrolled inflammation, calcification or endocarditis were detected [4]. The study is timely for several aspects. First, from a stent perspective the authors introduce a novel self-expanding stent design with a considerable low profile (35 mm) to accommodate wide RVOTs. Although no specific stent characterization and design parameters are provided (e.g. radial force, self-expansion properties), their results show in all but 1 case (in which the stent slightly migrated distally) appropriate adjustment to the native pulmonary anatomy suggesting accurate positioning. Importantly, no stent fractures or stent-strut damages were observed [4]. The use of a self-expanding stent concept is clinically highly relevant. To date, up to two-third of patients are not eligible to TPVR because of too large native or patched RVOTs that are not addressable with the current balloon-expandable Melody or Sapien valves [5] and creation of an appropriate landing zone by stent-implantation prior to valve implantation is often necessary. A number of devices and concepts are developed comprising the Edwards Alterra stent serving as a landing-zone for a Sapien valve, the Medtronic Harmony valve, the Venus-P valve (Venus Medtech/China), the Med-Zenith PT valve stent (Beijing Med-Zenith/China) and the Pulsta valve (TaeWoong Medical Co/Korea) [6]. Second, from a material selection and processing perspective, the choice of a dip-coating technique in combination with polycarbonate urethane allows for the fabrication of ultra-thin leaflets (thickness of 100–150 μm [4]) with relatively high Young’s modulus, which is key to enable a 'physiological' haemodynamic performance especially at low pulmonary pressures. For several decades, many attempts have been made to optimize polymers to produce durable and biocompatible materials for cardiovascular applications [3]. Numerous valves, fabricated from different polymers (e.g. silicon, polyurethanes and many others) and using various processing techniques were tested [3]. However, the majority has only shown limited durability and failed prematurely due to fatigue, thus preventing clinical translation. This is in addition to an elevated risk for thrombus formation, calcification and pannus overgrowth together with a substantial batch variability. Advanced chemical processing has overcome some of these problems lately. Compared to classical polyurethanes, polymers such as siloxane poly(urethane-urea)-based valves have demonstrated excellent in vitro durability of 600 million cycles (equivalent to 15 years) and absence of calcification and thrombus formation [3, 7] together with improved tear strength, creep resistance and non-permanent deformation [7]. In this context, a novel TAVR device utilizing heparinized polyurethane leaflets and a tactile-feedback concept for positioning is under development (Strait Access Technologies/South Africa) for the treatment of non-calcific aortic-valve disease [8]. Moreover, a clinical pilot-study (NCT03851068) has been initiated evaluating a Siloxane Poly(urethane-urea) Elastomer-based surgical aortic valve (Foldax/USA) and another clinical study currently investigates a biopolymer surgical mitral valve (NCT04717570). Interestingly, Lutter et al. [4] did not observe thrombus formation, even though no anti-coagulation or anti-platelet therapy was given. Although the follow-up period of 1 and 6 months is rather short- and longer-term observations are required, this may either be explained by the favourable tri-leaflet valve design enabling 'physiological' performance or by the fact that the valves were sterilized using glutaraldehyde. Similar to glutaraldehyde-fixed bioprostheses, it may be hypothesized that such sterilization may support the valves to develop initial anti-thrombogenic and anti-inflammatory layers. This could also explain the low degree of inflammatory cells and the absence of calcification in their explants. The risk of material calcification does not depend only on the leaflet surface but also on the polymer composition itself. However, the exact calcification mechanisms of polyurethanes are not completely clear yet, while several attempts have been made to elucidate these processes [3]. Examples are cation complexation and chelation, material fatigue, surface cracks and abrasion marks, which may ultimately lead to cellular infiltration and debris accumulation. This highlights the importance of an in-depth material characterization (e.g. polymer processing, mechanical properties and surface and topography evaluation) together with a comprehensive preclinical explant-assessment of such polymeric valves before safe clinical translation will be possible. Finally, and despite all current enthusiasm around polymeric valves, the key question of their overall functional remodelling capacity does remain to be investigated in regard to (i) long-term durability and performance; (ii) endothelialization capacity to prevent thrombus-formation; and (iii) resistance to infection (endocarditis), which also still represents a major issue in bioprosthetic TPVR (up to 5.8%) [1]. Lutter et al. [4] state that no endocarditis or calcification was detected and that endothelial cells were present on the stent. They however do not mention if and to what extend any leaflet endothelialization was observed. Although this was a pilot trial with few animals, a more detailed evaluation of such important remodelling parameters is mandatory to ultimately judge the translational potential of any new polymeric valve. In this regard, also other next-generation valve technologies (e.g. tissue and bioengineered valves) combined with latest manufacturing (e.g. 3D printing) and in silico technologies (e.g. computational modelling to forecast remodelling) are currently underway [7, 9, 10]. These have already proven their capacity to remodel, regenerate and even transform into native-like tissues while maladaptive phenomena (e.g. degeneration and calcification) are largely absent [7]. In line with the still valid ‘Ten Commandments’ by valve pioneer D.E. Harken in 1960, and inspired by nature, these characteristics ultimately define the optimal heart-valve replacement. Thus, while the race for the ideal heart-valve substitute is ongoing, only time will tell whether polymeric valves will prevail. Maximilian Y. Emmert has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme, grant agreement no. 852814 (TAVI4Life) and Sarah E. Motta is supported by the ERC grant TAVI4Life.