Review Article

Innovation and Development in Polymer Heart Valves: A New Era of Transcatheter Aortic Valve Replacement

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Abstract

Over the 20 years of the development of the transcatheter aortic valve replacement procedure, its indications, procedural techniques and device innovations have evolved to a significant degree. Nevertheless, while transcatheter aortic valve replacement has reached a relatively mature stage, research on devices continues. The emergence of the polymer heart valve (PHV) has added a new approach for the treatment of patients with aortic valve disease. This review summarises the development, manufacture and production of previously studied PHV materials. Clinical outcome data, attractive characteristics, recent advances and potential applications in the development of existing PHVs are also reported. Finally, the challenges and future research directions of PHV materials are discussed.

Keywords

Polymer heart valve, bioprosthesis, transcatheter aortic valve replacement, durability, review,

Received:

Accepted:

Published online:

DOI: https://doi.org/ 10.15420/ecr.2024.40

Disclosure: The authors have no conflicts of interest to declare.

Funding: This work was supported by the National Key R&D Program of China (2020YFC2008100); the Development and Transformation of New Technology and Construction of Precision Diagnosis and Treatment System for Transcatheter Interventional Diagnosis and Treatment of Structural Heart Diseases (2022YFC2503400); Research on Key Techniques of Minimally Invasive Treatment for Valvular Heart Diseases (2023-YBSF-105).

Acknowledgements: The authors thank Protext Editorial Services, US, for English language editing.

Correspondence: Jian Yang, Department of Cardiovascular Surgery, Xijing Hospital, 127 Changle West Rd, Xi’an, 710032, Shaanxi, China. E: yangjian1212@hotmail.com

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

After 20 years of unremitting development, the safety and efficacy of the transcatheter aortic valve replacement (TAVR) procedure has been confirmed in a large number of clinical studies and it is now considered a reliable treatment for patients with aortic valve (AV) disease.1–4 The most commonly used prostheses in AV replacement procedures can be categorised as mechanical prostheses and transcatheter heart valves (THV), both of which have their own characteristics.5–7 Notably, the leaflets of the current THVs are all hand-sewable using biological materials, such as bovine pericardium or pig pericardium, which is costly and relatively poor in durability with a relatively high risk of calcification and thrombosis.7–9 Therefore, developing a new THV with excellent durability and safety has been a challenge.

Polymer heart valves (PHVs) are already emerging in the field of THV engineering, with the goal of being able to provide a prosthesis that has the durability of the mechanical prosthesis without the need for long-term anticoagulant treatment. However, the first generation of PHVs had a number of limitations, including limited mechanical properties and poor biological and/or blood compatibility.10 New PHV materials have opened up new horizons in this field. They overcome the inadequate properties and closely mimic the tissue–mechanical behaviour of the native AV, thus contributing to the development of the ideal THV. The success of modern polymer manufacturing and modifications along with the development of new technologies (such as nanotechnology) has promoted the emergence of biomaterials with unique properties.11–13

In this review, we describe the development and specific characteristics of the first generation of PHVs, such as polysiloxane, polytetrafluoroethylene (PTFE) and polyurethane (PU)-based materials. We then discuss the development, manufacture and recent progress of the newer generation of PHVs. Finally, we discuss the challenges and future prospects of PHVs, providing new insights into the future development and clinical translation of PHV materials.

The First-generation Polymetric Compounds and Materials

The ideal prosthetic material should have good mechanical properties and biocompatibility, along with characteristics of antifatigue, anticoagulation, antidegradation and anticalcification. However, under the demanding dynamic conditions of a heart operation, most materials do not always maintain their mechanical properties. Although some polymer elastomers generally have better mechanical and tensile properties than hydrogels and native AV under static conditions, the combination of high toughness, fracture strain and strength is still inadequate in PHV materials. How they behave in vivo is worthy of more study. Commonly used polymer materials in first-generation PHVs include polysiloxane, PTFE and PU-based materials. This section discusses the structures, haemodynamics, durability, calcification, blood compatibility and biocompatibility of these materials. In addition, the shortcomings of the PHVs are evaluated.

Polysiloxane

Polysiloxane is a polymer with silicon–oxygen main-chains that ensure excellent biostability, biocompatibility and fatigue resistance (Figure 1A). Therefore, it is commonly used in the manufacture of medical devices, including prostheses, drainage system components and adhesives (antithrombotic coatings).14–17 In the 1950s, polysiloxane began to be applied to PHVs, but it failed to maintain long-term durability in subsequent coronary artery models.14,15 Although the first experience was not successful, many attempts have been made to develop PHVs using silicone elastomers.18–20 Later research products used a different silicone and – after >700 million cycles in vitro – they remained intact in accelerated fatigue tests. Among them, the thicker leaflets were assembled from silicone sponges, suture rings and steel bands. These early studies demonstrated that polysiloxane has relatively good biocompatibility, flexibility and fatigue resistance, but it has been associated with high rates of death and thrombus in clinical trials.15,20 The reason may be that the characteristics of the 58 Hz test, which was used frequently in preclinical in vitro trials, were inconsistent with the characteristics of the actual human body. Based on the fact that this material could not withstand the load generated by blood flow, silicone has been largely ignored for experimental PHV development since the 1980s. Although this material was not used in PHVs because it frequently resulted in prosthetic failure, it was still used occasionally in the later stages of in vitro research.

Polytetrafluoroethylene

PTFE is another promising polymeric compound (Figure 1B). Stable C–C and C–F bonds are formed in PTFE molecules, so it has a low surface tension and coefficient of friction, making the polymeric surface highly stable and bioinert.21 It is used in the manufacture of various medical devices, in particular prostheses, stents and vascular grafts for cardiovascular surgery.22 PTFE was originally used to manufacture the leaflets of the first prosthesis. A fully polymerised heart valve made of PTFE was used in 23 patients.23 However, the trial had a high mortality rate as well as various serious postoperative complications. Nistal et al. developed an expanded PTFE (ePTFE), whose porous, breathable structure opened new horizons in the field and was used to manufacture pulmonary prostheses for use in Ross surgery; however, the reports from the preclinical trials indicated that the leaflets tended to harden and calcify.24 Choi et al. reported that ePTFE PHV showed good prosthetic durability, but the gradual increase in pressure gradient (PG) led to degradation of the prosthesis.25 Roe et al. found that PHV made of 0.1 mm non-porous ePTFE showed a lower PG, but the inherent limitations of poor long-term durability prevented further expansion of the clinical application.18 In addition, Chang et al. implanted 0.1 mm ePTFE coated with choline phosphate into sheep. The mid-term outcome of the experiment found that the PHV was still thin and elastic, and the fibrous layer was observed only in the lower part of the PHV in the ventricular inflow tract.26 However, because of the material’s propensity to cause PHV calcification and/or thickening, resulting in mechanical dysfunction, current research and development are limited.

Polyurethane

PU is a polymer in the carbamate group, consisting of polyols (soft segments) and isocyanates (hard segments) (Figure 1C). The differences in chain flexibility and compatibility between the hard segments and the soft segments constitute the unique microphase separation structures, which in turn allow the flexible leaflets to move.27 By changing the ratio of soft and hard segments, it is possible to obtain polymers with various properties, thus broadening the applications in the field of medical devices.28 Braunwald successfully implanted a PHV made of flexible PU for the first time in a 44-year-old woman. The patient died 4 months after the operation as a result of arrhythmia.29 Studies on PU-based PHVs have reported that when its ether bond is oxidised, it leads to the hydrolysis of PU, increasing the possibility of biodegradation, calcification and thrombosis.30,31 Mackay et al. proposed a PHV design based on its being fixed in a flexible PU frame. The test report showed that the PG of PHV was similar to that of commercially available prostheses and that it had an equivalent service life of >10 years.32 However, its long-term biocompatibility and performance in vivo have not been evaluated. Subsequently, researchers evaluated the durability, thrombosis and function in vivo of PU PHV.33 The report showed that the PHV has good durability. In addition, the possibility of PU creep may affect the long-term durability of the prosthesis and eventually lead to its failure. The high molecular weight and high strength of polyisobutylene PU, which is 70% polyisobutylene soft-chain segments, have been designed to improve the creep resistance of PU.34

Figure 1: Characteristics of the First-generation Polymer Compounds Used in Polymer Heart Valve Construction

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Limitations of the First-generation Polymer Heart Valves

Although considerable achievements have been made in the field, many problems and challenges still exist in the design and manufacture of PHVs. The biggest contradiction is that, compared with the mechanical prosthesis, a gap still exists in the durability and service life of the first generation of PHVs, which also restricts their choice by younger patients. There are several possible reasons for this outcome. First, PHV failure caused by calcification is a problem that cannot be ignored in AV replacement. On the one hand, ePTFE is prone to inflammation and calcification in the human body.35 On the other hand, cyclic loading causes PU to be hydrolysed, whereby blood proteins and/or phospholipids passively accumulate and finally attract calcium ions.36 Then, the mobility of the PHV is limited due to the loss or rupture of the elasticity.37

Second, heart valve dysfunction may be caused by thrombosis. It is mainly caused by the incompatibility of PHV materials, which results in changes in fluid mechanics.38 In addition, due to the particularity of the chemical composition and surface structures of PHV, proteins in the blood spontaneously adsorb on the surface of the PHV, thus stimulating fibrin adhesion and platelet activation, leading to thrombosis.39 Subsequently, the chemical structures of PHV material change further, leading to biodegradation and further PHV failure.40 The main reasons are the low crystallinity of PHV materials, the presence of hydrophilic functional groups and the tendency of the macromolecular structure to be hydrolysed and oxidised.41 In addition, the ideal PHV material needs to have high tensile strength and moderate elasticity. The preceding studies show that, although the first-generation PHV has these properties, performance does not match the long-term cycle load, which results in long-term mechanical pressure overload. Consequently, the treatment does not provide the needed long-term durability and service life.18

Second-generation Polymer Heart Valve Materials

The search for PHV materials with a long service life and good histocompatibility has always been a research hotspot. In the past, numerous studies have reported successes and failures in developing the ideal PHV. However, all the studies focused on describing the design of PHV, and insufficient research on PHV requirements and polymer properties limited the development of PHV. With the progress of PHV material science, the success of modern polymer modification methods and the development of nanotechnology, the emergence of PHV materials with unique properties has been promoted. Among them, segmented copolymers and polymer nanocomposites are very representative today.13,42,43 This section describes the important characteristics of the second-generation PHVs, available clinical outcome data and potential applications now in development (Table 1).

Table 1: Materials, Mechanical Properties and Developmental Status of Second-generation Polymer Heart Valve Materials

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Foldax Tria (LifePolymer)

Foldax Tria (LifePolymer) consists of polymeric leaflets, a polyether ether ketone stent and a PTFE suture ring, with the leaflets made from a revolutionary biopolymer material called LifePolymer (Figure 2A). LifePolymer is a siloxane PU-urea material, a thermoplastic silicone-modified PU elastomer. The lack of well-organised hard segments is compensated for by increasing intermolecular hydrogen bonds and strengthening interfacial regions, thereby preventing deformation.44 The PHV has a self-expanding nitinol frame and a 10 mm sealing sleeve. The effective orifice area (EOA; 2.4 cm2) and the mean PG (7.3 mmHg) were similar to those of the THV during the hydrodynamics test in vitro.45

In addition, the PHV has excellent mechanical properties and has shown good biocompatibility in animal models. At present, in vitro tests of the Tria PHV show that, when the heart rates are up to 170 million beats, and if a person’s average heart rate is 70 BPM, Tria PHV can be used for approximately 35 years, which is better than the average service life of today’s THVs.46 Furthermore, Tria PHV has good blood compatibility, with minimal platelet deposition throughout a 60-minute study period, whereas the ePTFE PHV had significantly higher platelet attachment. Jenney et al. also compared eight 23 mm Tria PHV and two 25 mm PERIMOUNT Magna Ease (Edwards) implanted in a sheep model. Histopathological reports showed no surface thrombus on any of the prostheses.46

The 1-year follow-up outcomes of patients treated with surgical aortic valve replacement using Tria PHVs showed that the postoperative PG decreased significantly and the EOA increased significantly.12 Furthermore, the outcomes showed the good transportability and haemodynamics of the PHV and that no thrombosis or fibrosis occurred after 30 days.12 Patients implanted with PHVs did not need to take long-term anticoagulant drugs and their quality of life was greatly improved. In 2019, the Food and Drug Administration approved the use of Foldax’s Tria PHV in the clinic, marking a revolutionary advance since the emergence of prostheses 40 years ago. Currently, Tria PHV is undergoing larger clinical studies to prove its clinical applicability (NCT03851068).12,46

MitrAssist TRISKELE

MitrAssist TRISKELE is the first PHV product used globally for TAVR (Figure 2B). The PHV uses a polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer, which is covalently bonded to the polymer molecule as a suspension block. The POSS nanoparticles are combined with soft and hard PCU segments to form a single elastic matrix, which makes the nanocomposite resistant to hydrolysis, oxidation and calcification. The blood compatibility of POSS-PCU has previously been compared with that of PTFE.47 Compared with porous PTFE, POSS-PCU nanocomposites showed lower procoagulability and higher blood compatibility in terms of platelet activation, adhesion and whole blood response. Ghanbari et al. analysed the calcification sensitivity of POSS-PCU materials.48 The results showed that the calcium deposition on the POSS-PCU surface was negligible compared with the considerable calcium deposits detected on bovine pericardial and PU samples. In addition, the leaflet thickness of synthetic POSS-PCU is only one-third that of a bioprosthetic valve.

Sizes of the PHV are 23 mm, 26 mm and 29 mm, and the PHV anchoring area is located in the left ventricular outflow tract. In terms of the PHV design, the self-expanding and nickel–titanium wire riveted stent design can support the PHV stably, the unique torsion spring design can disperse the stress on the leaflets and extend the durability and the PHV can be fully retrieved and repositioned after being fully unfolded. The manufacturer briefly reported that the developed device met and substantially exceeded the durability requirements of the prosthesis (>200 million cycles).49 In comparative tests of hydrodynamic performance, the TRISKELE PHV has an EOA similar to that of the SAPIEN XT (Edwards) and the CoreValve (Medtronic) but has lower paravalvular regurgitation volume and ventricular energy loss.49 In animal experiments, TRISKELE PHV also showed excellent haemodynamic characteristics without affecting coronary arteries and its safety and efficacy were verified.49 Additionally, the comparative test of prosthetic durability also showed satisfactory results.49

Polynova

Polynova PHV is a second-generation PHV for TAVR, manufactured with poly(styrene-b-4-vinylbenzocyclobutene-b-isobutylene-b-styrene-b-4-vinylbenzocylcobutene) (xSIBS) (Figure 2C). Poly(styrene-b-isobutylene-b-styrene) (SIBS) is a thermoformed triblock copolymer with a microphase separation form and strong resistance to oxidation, hydrolysis and enzymatic hydrolysis.50 The material is covered with silicone and polyurethane and its central block consists of polyisobutylene and polystyrene. However, this material was prone to stress cracking, poor creep properties and fatigue failure. Then xSIBS was developed:51,52 xSIBS is a new thermosetting elastomer of polyolefin, which is cross-linked by the Diels–Alder reaction through a coupling reaction catalysed by benzocyclobutene.53 The material improves the mechanical properties on the basis of SIBS and effectively makes up for the deficiencies of the poor creep properties.

Polynova PHV is manufactured internally using a vacuum compression-forming process. The PHV is designed to be connected to a vacuum pipe to maintain a vacuum throughout the forming process, thus increasing the density and quality of the forming polymer.54 Previous studies have shown that Polynova PHV has a relatively small potential for thrombosis and for calcification sensitivity.55 The hydrodynamic test results showed that all prostheses had >400 million cycles.55 Compared to the PERIMOUNT and the Inovare prosthesis (Braile Biomedica), Polynova PHV has a larger EOA and a lower PG.55 However, Polynova PHV had a higher regurgitation fraction (11.87–21.28%). This result may be because the addition of a sleeve for a stent connecting to the leaflets may reduce the size of the neosinuses, resulting in delayed leaflet closure and increased regurgitation.

Strait Access Technology

Strait Access Technology’s (SAT) new prosthesis is a balloon-expandable PHV (Figure 2D). The SAT PHV features a hollow balloon for the placement of the prosthesis, allowing free blood flow without rapid pacing and haptic feedback to confirm the positioning during the procedure. The PHV consists of three parts: a stent, the integrated leaflets and a skirt. The leaflets are made of triblock polyurethane combining siloxane and a carbonate segment (CarboSil) polymer. In the early developmental stages, Gülan et al. tested the haemodynamic performance of SAT PHV.56 Compared with the Edwards PERIMOUNT, the PHV has thinner leaflets, a lower PG and a larger EOA. The in vitro results showed that SAT PHV could reach a predetermined 400 million cycles.42 Importantly, the PHV surface was almost completely free of calcification compared with acellular tissues.42 Similarly, Al Kayal et al. previously conducted experiments on the oxidative degradation and calcification of CarboSil material. Experimental results showed that no signs of calcification, macrophage infiltration or foreign giant cells were found in the material during the post-implant observation period.57 The product has been endorsed by the World Heart Federation and will commence clinical trials following regulatory approval.

Other Polymer Heart Valves

Hastalex is a new type of nanocomposite material based on the functionalised graphene-poly(carbonate-urea) urethane polymer (Figure 2E).13 The hydromechanical properties of Hastalex are largely dependent on the design of the prosthesis in general and on the design of the PHV in particular. However, the polymer’s high elasticity makes it possible to produce a thinner PHV, making it particularly promising for AV replacement applications. Previously, Ovcharenko et al. showed that Hastalex had higher ultimate tensile strength, better blood compatibility and anticalcification ability than ePTFE.13 As was the case with POSS-PCU, the introduction of carbon nanoparticles into the structure improved the polymer base, indicating its potential for use in cardiovascular surgery. Currently, only one prototype PHV based on Hastalex has been developed, with no data available on its hydrodynamic properties or results from the in vivo test.13 At the same time, mechanical properties are tested using cyclic loading, hysteresis testing and hydrodynamic testing to provide the overall benefit of the material.

PoliValve is another promising second-generation PHV manufactured with styrene-ethylene/propylene-styrene block copolymer (poly[styrene-block-ethylene/propylene-block-styrene]) (Figure 2F). The in vitro results showed that all prostheses had >500 million cycles.58 Meanwhile, the PHV met the minimum International Organization for Standardization standards for hydrodynamic performance. However, PoliValve has hydrodynamic differences based on leaflet thickness. With the increase of thickness, the EOA and the regurgitation fraction decreased significantly while the PG increased.58 In addition, Brubert et al. confirmed that the PHV has good blood compatibility because the polymer-like heparin coating reduced the possibility of surface thrombosis.59

Figure 2: Polymer Heart Valves Using Secondgeneration Materials for Transcatheter Aortic Valve Replacement

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Challenges and Prospects

Despite considerable progress and development in the field of interventional valve research, problems and challenges remain.60 First, compared with the mechanical prosthesis, there is still a gap in the durability and service life of PHV, restricting them as a choice for younger patients. At present, the biggest difficulty in the clinical application of PHV is that the haemodynamic performance of the material design differs greatly from that of the native AV or the adaptability of PHV to the actual situation in vivo is poor. Therefore, on the one hand, it is necessary to focus on the future of the ability of the PHV matrix materials to improve tear resistance under long-term stress. On the other hand, imitating the multilayer structure of the native AV and constructing biomimetic PHV with haemodynamic characteristics close to those of the human body should also be a future developmental trend.

Second, calcification is the main cause of PHV failure. For anticalcification modification of PHV, decellularisation may reduce the immunogenicity, thereby increasing the efficacy of decellularisation and improving the stability and integrity of the decellularised matrix. In addition, new cross-linking methods and alternative fixatives may reduce cytotoxicity and calcification.

Third, reducing the formation of thrombosis after the PHV is implanted will also help extend its service life. For PHV, mechanical differences cause blood turbulence through changes in PG and haemodynamics, which predispose the body to thrombosis and to mechanical stress at the opening of the PHV, leading to suture tearing. To solve this problem, high precision 3D printing, finite element analysis and deep learning may be used to model the process, thereby promoting the establishment of composite material models and the semiautomatic generation of new material models.

Conclusion

Treatment with an interventional valve represents the future developmental direction of structural heart disease. Therefore, a prosthesis with high durability must be the future trend. Over the past 20 years, the development of bioimplant technology has been remarkable. Compared with mechanical prostheses, the first-generation PHVs still have a gap in durability and service life. Since younger patients have a longer expected lifespan, the insufficient service life of PHVs may lead to the need for secondary surgery, thus restricting their application in this patient group. In contrast, PHV offers superior durability with no need for anticoagulation, a larger EOA, more precise quality control and lower costs. In this review, we have presented data on well-known polymers currently used in the manufacture of PHVs. The success of modern polymer manufacturing and modification methods, as well as the development of new technologies, has facilitated the emergence of biomaterials with unique properties. In particular, block copolymers and polymer nanocomposites are very important today. PHVs represented by the TRISKELE and Tria PHV are gradually entering the clinic. The relevant short- and mid-term clinical outcomes have confirmed that they have a certain efficacy and safety, but more clinical research data are needed. PHVs have undergone laboratory development, animal experiments and clinical implants. We expect them to demonstrate better long-term prognosis in the future and to play a more important role in the clinical field of interventional valve treatment.

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