EMT-Inducing Biomaterials for Heart Valve Engineering: Taking Cues from Developmental Biology

Abstract

Although artificial prostheses for diseased heart valves have been around for several decades, viable heart valve replacements have yet to be developed due to their complicated nature. The majority of research in heart valve replacement technology seeks to improve decellularization techniques for porcine valves or bovine pericardium as an effort to improve current clinically used valves. The drawback of clinically used valves is that they are nonviable and thus do not grow or remodel once implanted inside patients. This is particularly detrimental for pediatric patients, who will likely need several reoperations over the course of their lifetimes to implant larger valves as the patient grows. Due to this limitation, additional biomaterials, both synthetic and natural in origin, are also being investigated as novel scaffolds for tissue engineered heart valves, specifically for the pediatric population. Here, we provide a brief overview of valves in clinical use as well as of the materials being investigated as novel tissue engineered heart valve scaffolds. Additionally, we focus on natural-based biomaterials for promoting cell behavior that is indicative of the developmental biology process that occurs in the formation of heart valves in utero, such as epithelial-to-mesenchymal transition or transformation (EMT). By engineering materials that promote native developmental biology cues and signaling, while also providing mechanical integrity once implanted, a viable tissue engineered heart valve may one day be realized. A viable tissue engineered heart valve, capable of growing and remodeling actively inside a patient, could reduce risks and complications associated with current valve replacement options and improve overall quality of life in the thousands of patients who received such valves each year, particularly for children.

Tissue-Engineering Heart Valves

“…Synthetic polymers have the advantage in that they have predictable chemistry and their properties can be well-controlled [2]. Additionally, these materials are FDA (Food and Drug Administration) regulated and many have been approved in clinical applications [46]. The most commonly utilized synthetic polymers in tissue engineering include poly(glycolic acid) (PGA), poly(L-lactic acid) (PLLA), copolymer poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) (PEG), and polyhydroxyalkanoate (PHA).…”

“…It has been used as an autogeneic scaffold in heart valve tissue engineering [52]. Some advantages of using fibrin gel as a material for scaffold construction include that it is made from the patient's own blood, and also that it is readily Overview of tissue engineering heart valves [46].…”

“…Interestingly, cells from jugular veins also demonstrated higher initial collagen production, but the study showed that all cell lines had a marked drop-off in collagen, elastin and GAG synthesis with time. This finding suggests that there is a critical timeframe for seeded cells to be placed on scaffolds while they are still able to perform necessary protein synthesis and organization [46]. In the first long-term follow-up of a clinical application of a TEHV, Dohmen et al seeded a decellularized pulmonary allograft with cells isolated from saphenous vein and cultured in a bioreactor for two weeks.…”

Comparison of Mesenchymal Stem Cell Source Differentiation Toward Human Pediatric Aortic Valve Interstitial Cells within 3D Engineered Matrices

“…[63][64][65] bFGF plus EGF can trigger Wnt signaling pathway to induce epithelial-mesenchymal transition, which is an important process in the embryonic development of the heart valve. 66,67 The combination of bFGF and EGF can also maintain fibroblastic phenotype by inhibiting TGF-b-induced activation 68 and preserving multipotential properties of ovine BMMSC. 69 In addition, Song et al and Biver et al found that FGF2 could inhibit bone morphogenic protein-induced osteogenic differentiation of MSC.…”

Cellular Events Under Flow States Pertinent to Heart Valve Function

“…Critical valvular heart disease is a serious cardiovascular complication 38 . In infants, congenital heart defects occur in four to six infants for every 1000 births 39 .…”