3D printing technologies have the potential to revolutionize the manufacture of heart valves through the ability to create bespoke, complex constructs. In light of recent technological advances, we review the progress made towards 3D printing of heart valves, focusing on studies that have utilised these technologies beyond manufacturing patient-specific moulds. We first overview the key requirements of a heart valve to assess functionality. We then present the 3D printing technologies used to engineer heart valves. By referencing International Organisation for Standardisation (ISO) Standard 5840 (Cardiovascular implants - Cardiac valve prostheses), we provide insight into the achieved functionality of these valves. Overall, 3D printing promises to have a significant positive impact on the creation of artificial heart valves and potentially unlock full complex functionality.

Three-dimensional (3D) printing plays an important role in cardiovascular disease through the use of personalised models that replicate the normal anatomy and its pathology with high accuracy and reliability. While 3D printed heart and vascular models have been shown to improve medical education, preoperative planning and simulation of cardiac procedures, as well as to enhance communication with patients, 3D bioprinting represents a potential advancement of 3D printing technology by allowing the printing of cellular or biological components, functional tissues and organs that can be used in a variety of applications in cardiovascular disease. Recent advances in bioprinting technology have shown the ability to support vascularisation of large-scale constructs with enhanced biocompatibility and structural stability, thus creating opportunities to replace damaged tissues or organs. In this review, we provide an overview of the use of 3D bioprinting in cardiovascular disease with a focus on technologies and applications in cardiac tissues, vascular constructs and grafts, heart valves and myocardium. Limitations and future research directions are highlighted.

A 78-year-old male with severe symptomatic aortic stenosis was assessed by the heart-team as inoperable given the presence of a porcelain ascending aorta. Preprocedural cardiac computed tomography (CT) demonstrated a type-1 Sievers bicuspid aortic valve with a very large annular area at 1021 mm2, perimeter 115 mm, dimensions 37.1 × 36.0 mm and severe raphe and leaflet calcification. (Figure 1a and b). The inter-commissural distance at 4 mm above the annulus was 39.2 mm representing a flared anatomical configuration. Percutaneous implantation of a significantly overfilled balloon-expandable transcatheter heart valve (THV) was considered; however, in the setting of an extremely large aortic annulus beyond the manufacturer recommendations, questions remained regarding procedural safety and feasibility. A combination of CT-guided computational modeling and bench testing was performed to predict valve anchoring, frame expansion, THV leaflet coaptation, and paravalvular regurgitation (PVR). A 29 mm SAPIEN-3 device (Edwards Lifesciences, Irvine, CA) was overfilled by 8 ml and expanded on the bench with high-definition video documenting kinetics of THV expansion and relaxation (Supplemental Video 1). THV frame expansion and height were recorded using digital calipers (Figure 2a and b). The overexpanded THV was placed in a sealed 3D-printed static flow loop with physiological mass pressure (50 mmHg) to simulate leaflet coaptation in diastole. Visual assessment demonstrated complete leaflet coaptation with no leak within the flow loop (Figure 2c). The cardiac CT was analyzed for predictive computational modeling of the SAPIEN-3 balloon-expandable THV. The aortic root and left ventricle were segmented and meshed in Materialize Mimics (Leuven, Belgium). The 29 mm SAPIEN-3 geometry was created from micro-CT measurements with additional data from bench testing (Figure 2). Finite element analysis was performed using Abaqus 2020 (Johnston, USA). Material properties were defined as hyperelastic for native soft tissues, elastic for calcium nodules, and elastic for the stent and balloon which were extracted from previous studies.1Bosmans B. Famaey N. Verhoelst E. Bosmans J. Vander Sloten J. A validated methodology for patient specific computational modeling of self-expandable transcatheter aortic valve implantation.J Biomech. 2016; 49: 2824-2830Crossref PubMed Scopus (31) Google Scholar, 2Holzapfel G.A. Sommer G. Regitnig P. Anisotropic mechanical properties of tissue components in human atherosclerotic plaques.J Biomech Eng. 2004; 126: 657-665Crossref PubMed Scopus (320) Google Scholar, 3Tzamtzis S. Viquerat J. Yap J. Mullen M.J. Burriesci G. Numerical analysis of the radial force produced by the Medtronic-CoreValve and Edwards-SAPIEN after transcatheter aortic valve implantation (TAVI).Med Eng Phys. 2013; 35: 125-130Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The balloon was filled to +8 cc’s above nominal volume to simulate overexpansion of the THV followed by a balloon deflation step to account for tissue recoil (Figure 1c and Supplemental Video 2). CT simulation demonstrated an eccentrically expanded THV with average diameter of 30.4 mm and evidence of anchoring on the leaflet calcification (Figure 3a). PVR was evaluated following the stent deployment using computational fluid dynamics in Ansys Fluent (Canonsburg, USA). A nominal pressure in the aorta of 80 mmHg and 0 mmHg in the ventricle was applied to represent physiological diastolic conditions. The highest velocity PVR jets were predicted to originate anterolaterally (Figure 3b). The patient was successfully treated with a 29 mm SAPIEN-3 THV deployed with 8 ml of additional volume (Figure 1d). Post-dilatation was performed with the same overfilled balloon volume to optimize frame expansion. Intraprocedural transoesophageal echocardiography demonstrated trivial valvular and mild PVR predominately located at the anterolateral aspect of the frame (Figure 3d and Supplemental Video 3). Post-transcatheter aortic valve replacement (TAVR) CT highlighted an eccentrically expanded frame with comparable dimensions to CT modeling (Figure 3c). To our knowledge, this is the largest aortic annulus successfully treated with a THV. It should be emphasized that this single report does not support the routine treatment of extremely large annuli with TAVR, which requires further clinical evaluation. Our case provides new insight into the potential role of CT-guided computational modeling to predict and optimize outcomes in patients undergoing TAVR for complex aortic valve disease. Future studies are needed to assess the ability of CT-guided computational modeling to guide TAVR procedural strategy across the spectrum of annuli size, THV devices, and procedural endpoints. Consent given by the patient for publication of this case. Dr Abdul Ihdayhid is supported by the National Heart Foundation and National Health and Medical Research Council of Australia Scholarships.

Heart valve tissue engineering (HVTE) aims to provide living autologous heart valve implants endowed with regenerative capabilities and life‐long durability. However, fabrication of biomimetic scaffolds capable of providing the required functionality in terms of mechanical performance and tunable porosity to enable cellular infiltration remains a major challenge. Here, the additive manufacturing of bioinspired, spatially heterogeneous, tubular scaffolds enclosing the leaflets, inter‐leaflet triangles, and their interface for in situ HVTE using melt electrowriting (MEW) is demonstrated. The innovative platform enables the digital fabrication of scaffolds with ad hoc architecture (e.g., tunable location, specific fiber pattern, and orientation) and customizable geometry via a custom‐made control software. The user‐friendly interface allows for the definition of areas of the scaffold with specific patterns to obtain properties such as tunable J‐shaped stress–stain curve and anisotropy typical of the heart valve leaflet, compliant inter‐leaflet triangles, and reinforced curvilinear boundary between them. Heterogeneous, tubular, heart valve MEW scaffolds are then embedded with a microporous elastin‐like recombinamer (ELR) hydrogel to develop a soft‐network composite favoring cell infiltration and ensuring hemocompatibility. The acute systolic hemodynamic functionality of the MEW/ELR composite satisfies the ISO 5840 requirements, under aortic and pulmonary conditions.

Interfaces within biological tissues not only connect different regions but also contribute to the overall functionality of the tissue. This is especially true in the case of the aortic heart valve. Here, melt electrowriting (MEW) is used to engineer complex, user-defined, interfaces for heart valve scaffolds. First, a multi-modal imaging investigation into the interfacial regions of the valve reveals differences in collagen orientation, density, and recruitment in previously unexplored regions including the commissure and inter-leaflet triangle. Overlapping, suturing, and continuous printing methods for interfacing MEW scaffolds are then investigated for their morphological, tensile, and flexural properties, demonstrating the superior performance of continuous interfaces. G-codes for MEW scaffolds with complex interfaces are designed and generated using a novel software and graphical user interface. Finally, a singular MEW scaffold for the interfacial region of the aortic heart valve is presented incorporating continuous interfaces, gradient porosities, variable layer numbers across regions, and tailored fiber orientations inspired by the collagen distribution and orientation from the multi-modal imaging study. The scaffold exhibits similar yield strain, hysteresis, and relaxation behavior to porcine heart valves. This work demonstrates the ability of a bioinspired approach for MEW scaffold design to address the functional complexity of biological tissues.