Elsevier

Biomaterials

Volume 288, September 2022, 121756
Biomaterials

A biomimetic multilayered polymeric material designed for heart valve repair and replacement

Research Strategy of the presented work: Native heart valve leaflet tissue is used as the reference. A biomimetic multilayered material is designed and fabricated as the polymeric leaflet substitution. This material can be used either as the key component of a polymeric valve prosthesis for heart valve replacement, or as the cardiovascular patch for heart valve repair. Leaflet architecture is adapted with permission. Copyright 2012, Wolters Kluwer Health, Inc.
https://doi.org/10.1016/j.biomaterials.2022.121756Get rights and content

Highlights

  • Biostable polymers have been used to fabricate a multilayered leaflet-like structure that mimics native tissue.

  • Mechanical performance of this multilayered material better resembles native leaflets.

  • This multilayered material displayed superior biostability in an accelerated oxidization environment.

  • In vivo subcutaneous model confirmed the superior biocompatibility of this material compared to commercial alternatives.

Abstract

Materials currently used to repair or replace a heart valve are not durable. Their limited durability related to structural degeneration or thrombus formation is attributed to their inadequate mechanical properties and biocompatibility profiles. Our hypothesis is that a biostable material that mimics the structure, mechanical and biological properties of native tissue will improve the durability of these leaflets substitutes and in fine improve the patient outcome. Here, we report the development, optimization, and testing of a biomimetic, multilayered material (BMM), designed to replicate the native valve leaflets. Polycarbonate urethane and polycaprolactone have been processed as film, foam, and aligned fibers to replicate the leaflet's architecture and anisotropy, through solution casting, lyophilization, and electrospinning. Compared to the commercialized materials, our BMMs exhibited an anisotropic behavior and a closer mechanical performance to the aortic leaflets. The material exhibited superior biostability in an accelerated oxidization environment. It also displayed better resistance to protein adsorption and calcification in vitro and in vivo. These results will pave the way for a new class of advanced synthetic material with long-term durability for surgical valve repair or replacement.

Introduction

Valvular heart disease (VHD) affects more than 100 million people worldwide and is associated with substantial morbidity and mortality [[1], [2], [3]]. Although the incidence of VHD is high, current therapeutic approaches are limited to valve replacement or repair, either through surgical or percutaneous approaches [4,5]. Two types of artificial valves are commercially available for valve replacement: mechanical and bioprosthetic valves. Mechanical valves have higher durability, but their rigid metal leaflets and limited geometric design create non-physiological flow and predispose to thrombosis and related embolic events [6]. Consequently, patients treated with mechanical valve replacement require lifelong anticoagulation therapy and thus are at increased risk of adverse events related to bleeding. Moreover, the complication specific to mechanical valves are devastating, and the permanent neurological sequelae of embolic or hemorrhagic stroke can result in catastrophic changes in the patients’ life [[7], [8], [9]]. Bioprosthetic valves, on the other hand, are made with fixed exogenous cardiac tissue and have better biocompatibility without lifelong anticoagulant therapy. However, their tissue processing conditions and inadequate material properties make them susceptible to calcification and structural valve degeneration (SVD) in 15 years, depending on patient ages, co-morbidities and demographics, etc. [10,11]. Durability issues are attributed to calcification and fatigue-induced structural deterioration of the tissue leaflets, caused in part by localized leaflet damage at stressed regions [12,13]. Valve repair becomes an alternative treatment option for patients with incompetent aortic valves, which preserves the native valve tissue, and decreases the risks of mortality and infection [14]. Such repairs frequently require the use of polymeric or tissue-derived patches, both of which have intrinsic limitations that affect their long-term durability and mechanical performance, leading to structural degeneration (SD) of the repaired valve leaflet and subsequent reoperation [[15], [16], [17], [18], [19], [20], [21], [22], [23]]. Pavy et al. summarized that the discrepancy between the elastic modulus of the patch and native tissue is linked to severe aortic stenosis and prosthetic material failure by alteration of pressure and flow dynamics throughout the valve [24,25]. This mismatch results in perturbed blood flow and turbulence, which may lead to thrombosis, and which also produces pulsatile mechanical stresses at anastomoses leading to suture line disruption [26]. Martin and Sun utilized a computational modeling to identify adverse impacts of these mismatched mechanical properties: leaflet substitutes with isotropic behavior and unmatched elastic property resulted in higher leaflet stresses and accelerated fatigue damage along the commissures and suture attachments [27,28]. This phenomenon is also in line with clinical findings that mechanical failures of bioprosthetic valves are often associated with leaflet tears near the commissures and suture attachments. Moreover, the adjacent native tissue has to biologically remodel itself to compensate for this mechanical discrepancy, and the resulting excessive remodeling (thickening) narrows the valve opening and occludes the blood flow [29].

Different groups have attempted to fabricate synthetic valve substitutes that can more closely resemble native tissue, but with limited success [[30], [31], [32], [33]]. Early studies explored the use of polymeric materials such as silicon and polyurethanes due to their favorable mechanical properties and chemically defined composition, but clinical translation was hindered by premature degradation, thrombosis, and calcification [34]. Advances in polymer synthesis have recently led to new generations of polyurethanes with more favorable thrombogenic and calcification profiles, such as polycarbonate urethane (PCU) and polyether urethane urea (PEUU), that show clinical promise [35]. More recently, hydrogel-based valve substitutes fabricated from materials such as a polyvinyl alcohol (PVA) and poly(ethylene glycol) (PEG) have also been examined due to their flexible mechanical and biological properties [30,31]. However, the degradable nature of hydrogels and lack of durability data makes this family of materials questionable as a long-term valve substitute [32]. In addition, many of these proposed polymers or polymer composites do not account for the unique three-layer architecture of the native leaflets. Native leaflets have a highly organized architecture with three specific layers. Leaflet mechanical stiffness and nonlinear stress-strain behavior are attributed to two surface fibrous layers: the fibrosa and ventricularis [36]. The middle layer, the spongiosa, accommodates the shear forces between the two surface layers and absorbs the load during valve opening and closing [37]. This unique architecture is critical to offering mechanical properties that withstand high trans-valvular pressures with low flexural stiffness. Masoumi et al. developed a tri-layered scaffold to mimic the structural and anisotropic mechanical characteristics of the native leaflet [33]. However, this tri-layered scaffold was fabricated from a poly (glycerol sebacate) (PGS)-polycaprolactone (PCL) composite that degraded at a fast rate with a significant loss of mechanical strength in 4 weeks. Despite aiming at replicating the valve architecture, this polymer composite was not a mechanically stable option for clinical use.

In summary, the reasons for those unideal performances of the academic trials may be attributed to these factors: 1) focusing on tissue engineering and regenerative medicine to create living autologous heart valve leaflets are still far from ideal despite many decades of research, mainly related to the lack of control of the balance between polymer degradation and tissue formation in-vivo: the mechanical properties of the applied degradable materials change over time, leading to a loss of mechanical stability and a progressing mismatch between artificial leaflet substitutes and the native leaflets, if the degradation and regeneration are unexpected or out of control; 2) some attempts did not fully replicate the complex structure-function relationship of the native valves, and neglect the essential role of the architecture in the functionality; 3) mechanical data such as ultimate tensile strength and break strain, were recorded at a higher strain level than the physiological level, which is not appropriate to assess the mechanical performance under physiological conditions; 4) the impact of the cyclic deformation that the material is exposed in a valve leaflet position was not fully studied; Hence, there continues to be a significant need for the development of durable valve materials that can mechanically and structurally mimic native tissue, and ultimately improve the outcomes of the surgical and transcatheter treatment of valvular heart disease patients. In this present work, we aim to fabricate a stable, functional and biomimetic material based on advanced polymer composites. Our biomimetic, multilayered material (BMM) was fabricated with a biostable polymer as the main composition, using a combination of solution casting, electrospinning and lyophilization techniques to form three distinct layers. We expect to tailor the proper mechanical properties and anisotropic performance of BMM, through fabricating the composite with the designed structure replicating the architecture of the native valve, in order to maintain its matched properties and durable functionality in the long term. This material may possess potential for translation towards new cardiovascular patches for surgical valve repair and new polymeric heart valve prostheses for surgical and transcatheter valve replacement.

Section snippets

Materials

Carbothane™ AC-4075A, Polycarbonated-based polyurethane (PCU) (Lubrizol, Wilmington, Massachusetts, Mw = 480 kDa) was dissolved in dimethylacetamide (DMAC) (Acros Organics, Fair Lawn, New Jersey). Polycaprolactone (PCL, Mw = 80,000; Sigma-Aldrich, St. Louis, Missouri) was used to create fibers and dissolved with a mix of chloroform (Sigma-Aldrich, St. Louis, Missouri) and methanol (Fisher Scientific, Hampton, New Hampshire) with a 3:1 M ratio. Three commercially available patches were selected

Structure

The BMM was designed as a tri-layer polymeric structure that was specifically developed to mimic the tri-layer anatomy of the native valve (Fig. 1A): an F-mimic layer, an S-mimic layer and a V-mimic layer. Fig. 1B shows that the aligned PCL fibers predominantly exist with a highly-orientated distribution, while random PCL fibers are electrospun with a random direction (Fig. 1C). The cross-section image (Fig. 1D) shows the aligned fibers were embedded in the PCU film to form two fiber-enhanced

Discussion

Heart valve leaflets have a highly organized architecture with three specific layers. The fibrosa and ventricularis consist of circumferentially oriented collagen fibers and radially oriented elastin sheets, which constitute their primary load-bearing properties [36]. The spongiosa is inherently soft and compliant with a much lower stiffness. It acts as a cushion, absorbing the load resulting in minimal stress [37]. In this present work, we designed and fabricated a biomimetic, multilayered

Conclusion

Materials currently used for heart valve repair or replacement display very limited durability related to their suboptimal mechanical and biocompatibility performance. There is a clinical need for a new type of biostable material that can achieve better durability after implantation in patients. In this work, our team developed a polymeric, biomimetic multilayered material that replicates the structure-function driven architecture of native valve leaflets via a series of processing methods:

Credit author statement

Mingze Sun: developed the BMM and fabrication process, designed and performed the experiments, analyzed and interpreted the data, draft the original manuscript. Mohamed Elkhodiry: verified, analyzed and interpreted the data; review and editing the manuscript. Lei Shi: developed the flexural mechanical test, performed the dest, analyzed and interpreted the data, Yingfei Xue: designed and performed the in vitro biocompatibility test, analyzed and interpreted the data. Maryam H Abyaneh: selected

Funding

This project was supported by the Thoracic Surgery Foundation Research Award (DK); the Congenital Heart Defect Coalition Research Grant (DK); the National Institutes of Health 1R01HL155381-01 (DK) and R01HL143002 (GF); the American Heart Association Transformational Project Award [20TPA35310049] (DK).

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mingze Sun has patent Biomimetic polymeric composite for heart valve repair pending to The Trustees of Columbia University in the City of New York. David Kalfa has patent Biomimetic polymeric composite for heart valve repair pending to The Trustees of Columbia University in the City of New York.

Acknowledgement

Authors would like to thank Dr. Hyesung Kim and Dr. Kam Leong for the help with electrospinning, Stephanie Nicole McCartney and Dr. Ngai Yin Yip for the help with contact angle measurement, Dr. Philippe Chow for the help with molecular weight measurement.

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