Introduction: Heart valve disease is an increasingly prevalent and clinically serious condition. There are no clinically effective biological diagnostics or treatment strategies. The only recourse available is replacement with a prosthetic valve, but the inability of these devices to grow or respond biologically to their environments necessitates multiple resizing surgeries and life-long coagulation treatment, especially in children. Tissue engineering has a unique opportunity to impact heart valve disease by providing a living valve conduit, capable of growth and biological integration.Areas covered: This review will cover current tissue engineering strategies in fabricating heart valves and their progress towards the clinic, including molded scaffolds using naturally derived or synthetic polymers, decellularization, electrospinning, 3D bioprinting, hybrid techniques, and in vivo engineering.Expert opinion: Whereas much progress has been made to create functional living heart valves, a clinically viable ...

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Current progress in tissue engineering of heart valves: multiscale problems, multiscale solutions

Introduction: Heart valve disease is an increasingly prevalent and clinically serious condition. There are no clinically effective biological diagnostics or treatment strategies. The only recourse available is replacement with a prosthetic valve, but the inability of these devices to grow or respond biologically to their environments necessitates multiple resizing surgeries and life-long coagulation treatment, especially in children. Tissue engineering has a unique opportunity to impact heart valve disease by providing a living valve conduit, capable of growth and biological integration. Areas covered: This review will cover current tissue engineering strategies in fabricating heart valves and their progress towards the clinic, including molded scaffolds using naturally derived or synthetic polymers, decellularization, electrospinning, 3D bioprinting, hybrid techniques, and in vivo engineering. Expert opinion: Whereas much progress has been made to create functional living heart valves, a clinically viable product is not yet realized. The next leap in engineered living heart valves will require a deeper understanding of how the natural multi-scale structural and biological heterogeneity of the tissue ensures its efficient function. Related, improved fabrication strategies must be developed that can replicate this de novo complexity, which is likely instructive for appropriate cell differentiation and remodeling whether seeded with autologous stem cells in vitro or endogenously recruited cells.

Current progress in tissue engineering of heart valves: multiscale problems, multiscale

Bioprinting a cardiac valve

Microarray analyses to quantify advantages of 2D and 3D hydrogel culture systems in maintaining the native valvular interstitial cell phenotype

Endothelialization of cardiovascular devices

In-body tissue architecture--a novel and practical regeneration medicine technology--can be used to prepare a completely autologous heart valve, based on the shape of a mold. In this study, a three-dimensional (3D) printer was used to produce the molds. A 3D printer can easily reproduce the 3D-shape and size of native heart valves within several processing hours. For a tri-leaflet, valved conduit with a sinus of Valsalva (Biovalve type VII), the mold was assembled using two conduit parts and three sinus parts produced by the 3D printer. Biovalves were generated from completely autologous connective tissue, containing collagen and fibroblasts, within 2 months following the subcutaneous embedding of the molds (success rate, 27/30). In vitro evaluation, using a pulsatile circulation circuit, showed excellent valvular function with a durability of at least 10 days. Interposed between two expanded polytetrafluoroethylene grafts, the Biovalves (N = 3) were implanted in goats through an apico-aortic bypass procedure. Postoperative echocardiography showed smooth movement of the leaflets with minimal regurgitation under systemic circulation. After 1 month of implantation, smooth white leaflets were observed with minimal thrombus formation. Functional, autologous, 3D-shaped heart valves with clinical application potential were formed following in-body embedding of specially designed molds that were created within several hours by 3D printer.

In-body tissue-engineered aortic valve (Biovalve type VII) architecture based on 3D printer molding.

We developed an autologous, trileaflet tissue valve (“biovalve”) using in-body tissue architecture technology to overcome the disadvantages of current bioprosthetic valves. We designed a novel biovalve with a balloon-expandable stent: the stent biovalve (SBV). This study evaluated the technical feasibility of sutureless aortic valve replacement using the SBV in an orthotopic position, as well as the functionality of the SBV under systemic circulation, in an acute experimental goat model. Three adult goats (54.5–56.1 kg) underwent sutureless AVR under cardiopulmonary bypass (CPB). The technical feasibility and functionality of the SBVs were assessed using angiography, pressure catheterization, and two-dimensional echocardiography. The sutureless AVR was successful in all goats, and all animals could be weaned off CPB. The mean aortic cross-clamp time was 45 min. Angiogram, after weaning the animals off CPB, showed less than mild paravalvular leakage and central leakage was not detected in any of the goats. The mean peak-to-peak pressure gradient was 6.3 ± 5.0 mmHg. Epicardial two-dimensional echocardiograms showed smooth leaflet movement, including adequate closed positions with good coaptation; the open position demonstrated a large orifice area (average aortic valve area 2.4 ± 0.1 cm2). Sutureless AVR, using SBVs, was feasible in a goat model. The early valvular functionalities of the SBV were sufficient; future long-term experiments are needed to evaluate its durability and histological regeneration potential.

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Sutureless aortic valve replacement using a novel autologous tissue heart valve with stent (stent biovalve): proof of concept

We designed a novel method for constructing an autologous heart valve with a stent, called a stent-biovalve. In constructing completely autologous heart valves, named biovalves, which used in-body tissue architecture technology, tissues for leaflets were formed via ingrowths into narrow apertures in the preparation molds, frequently leading to delayed or incomplete biovalve preparation. In this technique, self-expandable nitinol stents after everting were mounted on an acrylic column-shaped part and partially covered with an acrylic cylinder-shaped part with three slits. This assembled mold was placed into subcutaneous abdominal pouches in beagles or goats for 4 weeks. Upon removing the acrylic parts after harvesting and trimming of capsulated tissues, a tubular hollow structure with three pocket-flaps of membranous tissue rigidly fixed to the stent's outer surface was obtained. Then, the stent was turned inside out to the original form, thus moving the pocket-flaps from outside to the inside. Stent-biovalves with a sufficient coaptation area were thus obtained with little tissue damage in all cases. The valve opened smoothly, and high aperture ratio was noted. This novel technique was thus highly effective in constructing a robust, completely autologous stent-biovalve with adequate valve function.

Preparation of an autologous heart valve with a stent (stent-biovalve) using the stent eversion method

In this study, self-expanding valved stents were prepared by in-body tissue architecture technology. As molds, plastic rods (outer diameter; 14 or 25 mm), mounted with specially designed self-expanding stents, whose strut was a combination of two wavy rings and three pillars, were embedded into the subcutaneous pouches of goats or beagles for 1 month. Upon harvesting, the molds were fully encapsulated with membranous connective tissues, in which the stent strut was completely embedded. The tubular tissues with the stents were obtained by removing the internal rods. About a half of the tubular tissues as a leaflet part was folded inside the remaining tubular tissues having ring strut as a conduit part. When the overlapped tubular tissues were fixed at the three pillars, two different-sized self-expanding valved stents (internal diameter; 14 or 25 mm) with autologous tubular leaflet tissues were obtained as Stent-Biovales. After shape formation of the leaflets at the closed form, regurgitation rate was approximately 5 and 22 % at pulmonary and aortic condition, respectively. The Stent-Biovalves developed here may be useful as a heart valve for patients undergoing transcatheter heart valve implantation.

Development of self-expanding valved stents with autologous tubular leaflet tissues for transcatheter valve implantation

We have used in-body tissue architecture technology to develop an autologous valved conduit with intact sinuses of Valsalva (biovalve). In this study, we fabricated three different forms of biovalves and evaluated their function in vitro using a mock circulation model to determine the optimal biovalve form for aortic valve replacement. A cylindrical mold for biovalve organization was placed in a dorsal subcutaneous pouch of a goat, and the implant that was encapsulated with connective tissue was extracted 2 months later. The cylindrical mold was removed to obtain the biovalve (16 mm inside diameter) that consisted of pure connective tissue. The biovalve was connected to a pulsatile mock circulation system in the aortic valve position. The function of the three biovalves (biovalve A: normal leaflets with the sinuses of Valsalva; biovalve B: extended leaflets with the sinuses of Valsalva; biovalve C: extended leaflets without the sinuses of Valsalva) was examined under pulsatile flow conditions using saline. In addition, the mock circuit was operated continuously for 40 days to evaluate the durability of biovalve C. The regurgitation rate (expressed as a percent of the mean aortic flow rate during diastole) was 46% for biovalve A but only 3% for biovalves B and C. The durability test demonstrated that even after biovalve C pulsated more than four million times (heart rate, 70 bpm; mean flow rate, 5.0 L/min; mean aortic pressure, 92 mm Hg), stable continuous operation was possible without excessive reduction of the flow rate or bursting. The developed biovalve demonstrated good function and durability in this initial in vitro study.

Hirohito Sumikura

Papers

In-body tissue-engineered aortic valve (Biovalve type VII) architecture based on 3D printer molding.

Sutureless aortic valve replacement using a novel autologous tissue heart valve with stent (stent biovalve): proof of concept

Preparation of an autologous heart valve with a stent (stent-biovalve) using the stent eversion method

Development of self-expanding valved stents with autologous tubular leaflet tissues for transcatheter valve implantation

In Vitro Evaluation of a Novel Autologous Aortic Valve (Biovalve) With a Pulsatile Circulation Circuit