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

Abstract

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.

Keywords: 3D tissue printing; biomechanics; material heterogeneity; stem cells.

Figure 1

Functional anatomy and heterogeneous composition of the aortic root. (A) The aortic root is a complex structure consisting of the leaflets and other structures, including the Sinus of Valsalva, commissure, sinutubular junction, ventriculo-aortic junction, and leaflet attachment. Figure from and reprinted with permission. (B) Movat depiction of the ECM componets within the three layers of the aortic leaflet. Collagen is found throughout the valve, but it is packed tightly and aligned circumferentially in the fibrosa. Elastin is radially-aligned and predominately exists in the ventricularis. GAGs are mainly found in the spongiosa. Endothelial cells line the fibrosa and ventricularis sides, and valvular interstitial cells are found throughout the valve. (C) Biomechanical forces acting on the aortic root. During diastole, leaflets are stretched to form the coaptation and prevent backflow. Leaflets experience tensile strain and stress from the aortic pressure. In systole, leaflets are flexed open and experience both oscillatory and laminar shear stresses. Figure adapted from .

Figure 2

Selected examples of TEHVs. (A) Electrospun PEGdma-PLA fibers onto a valve-shaped target. Figure adapted from with permission from Elsevier. (1) Copper valve mold/target. (2) Mold partially covered with electrospun material (white). (B) 3D bioprinted TEHV using PEGDA. Figure adapted from with permission. (1) 3D model of the scanned porcine heart valve. (2) 3D printed valve showing complex anatomical shapes. (3) Various sizes of the 3D printed heart valves. (C) Self-assembled fibroblast sheets were cut into leaflets and sutured onto a stent. Figure adapted from with permission. (1) Cut-outs for the leaflets. (2) Pieces of leaflets cut out from self-assembled fibroblast sheet. (3-4) Bottom and top views of the stented valve. (D) PU-wrapped valve-shaped mold implanted in vivo to form fibrous tissue. Figure adapted from with permission. (1) Silicone valve-shaped rod used as a mold. (2) A sheet of PU was wrapped around the rod and implanted subcutaneously. (3) Fibrous tissue formation after implantation. (4) Close up of the leaflets formed. Arrowheads denote places where the membrane was cut to form the leaflets.