Integrating Principles of Developmental Biology in Tissue Engineering of Heart Valves

Abstract

Approximately eight out of every thousand infants are born with congenital heart disease. The majority of these defects involve malformations or absence of the pulmonary valve and main pulmonary arteries. Although repair early in life is possible, the procedure often requires the use of a replacement valve. Current replacement options include prosthetic and bioprosthetic valves; however, these replacements have limited durability and are subject to calcification, thrombosis and a lack of growth potential [1]. Children, therefore, face an ongoing morbidity due to the limitations of these replacement valves and must endure multiple follow-up operations in order to place progressively larger valves to accommodate their growth. Tissue engineering offers the potential to create a living valve with the capacity for growth and self-repair, and which is resistant to infection. Tissue engineering is defined as an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain or improve function [2]. This approach is based on seeding autologous cells onto biodegradable scaffolds or decelullarized biological matrices in order to provide temporary structural support and organization until the cells synthesize their own extracellular matrix. Previous studies by our group and others have demonstrated in vivo results culminating in the creation of single-valve leaflets [3], vascular grafts [4,5] and trileaflet-valved conduits [6–11]. These tissue-engineered heart valve (TEHV) structures have been created using vascular cells [3,4,6–9], umbilical bloodderived endothelial progenitor cells [11] and noncirculating bone marrow-derived mesenchymal stem cells [12,13] as cell sources. Our group and others have also demonstrated results in preliminary in vivo experiments. However, many questions remain unanswered: • What is the optimal cell source? • How will the scaffold material influence tissue growth and allow favorable scaffold cell and extracellular matrix interactions? • What in vitro conditions provide the most cell growth? • What is the timeframe for in vivo maturation? The ideal heart valve replacement would not only be biocompatible, readily available and incredibly durable, but also have the potential for growth [14]. Although the ultimate goal of TEHV is to recapitulate the matrix and cells found in the native tissue, variabilities exist within the potential strategies and sources of cells. A widely accepted paradigm of tissue engineering comprises of a scaffold that is preseeded with cells, followed by an in vitro stage of tissue formation typically conducted in a bioreactor (that recapitulates a physiological metabolic and mechanical environment) and, following subsequent implantation of the construct, an in vivo stage of tissue growth and remodeling [15].