Cardiovascular tissue engineering

Tissue engineering is a broad term describing a set of tools at the interface of the biomedical and engineering sciences that use living cells or attract endogenous cells to aid tissue formation or regeneration, and thereby produce therapeutic or diagnostic benefit. In the most frequent paradigm, cells are seeded on a scaffold composed of synthetic polymer or natural material (collagen or chemically treated tissue), a tissue is matured in vitro, and the construct is implanted in the appropriate anatomic location as a prosthesis [1–4]. A typical scaffold is a bioresorbable polymer in a porous configuration in the desired geometry for the engineered tissue, often modified to be adhesive for cells, in some cases selective for a specific cell population. Either application-specific differentiated or undifferentiated (stem) cells are used [5,6]. The first phase is the in vitro formation of a tissue construct by placing the chosen cells and scaffold in a metabolically and mechanically supportive environment with growth media (in a bioreactor), in which the cells proliferate and elaborate extracellular matrix (ECM). In the second phase, the construct is implanted in the appropriate anatomic location, where remodeling in vivo is intended to recapitulate the normal functional architecture of an organ or tissue. The key processes occurring during the in vitro and in vivo phases of tissue formation and maturation are (1) cell proliferation, sorting and differentiation; (2) ECM production and organization; (3) degradation of the scaffold; and (4) remodeling and potentially growth of the tissue. The general paradigm of tissue engineering is illustrated in Fig. 1. Since the cells of the implant can contact the surrounding tissues of the recipient, this approach is termed an ‘‘open-system.’’ In contrast, ‘‘closed-system’’ devices have therapeutic cells that are encapsulated or otherwise isolated from the recipient’s blood or tissues by semipermeable polymer membranes. This permits nutrients, wastes, drugs or hormones to pass yet keeps larger molecules such as the recipient’s antibodies or inflammatory/immune cells away, thus protecting the cells from degradation. Closed-system devices are used to deliver biologically active agents (such as drugs) to a restricted anatomic site (localized, controlled drug delivery) or to serve as extracorporeal cell-containing devices for renal, hepatic or pancreatic assist. Some tissue engineering applications use one of various ‘‘incomplete’’ paradigms, in which certain steps in the general paradigm are omitted (Fig. 2). For example, the cell-seeded scaffold model (see Fig. 2A) is exemplified by endothelial seeding of a synthetic or tissue derived vascular graft prior to implantation [7,8]. The cell transplant model (see Fig. 2B) is exemplified by one approach to myocardial tissue engineering in which injected cells (myocytic or with myocyte potential) differentiate and proliferate in or near damaged myocardium [9,10]. Investigators attempting to provide engineered heart valves and vascular grafts have utilized decellularized tissue scaffolds that attract endogenous cells (see Fig. 2C) to repopulate and remodel an altered tissue that preserves architectural and chemical information [11,12]. In vitro tissue ‘‘equivalents’’ (see Fig. 2D) may provide tools to understand normal physiological processes, study pathogenesis of disease and provide diagnostic and therapeutic tools (e.g., patterned cell cultures to probe cellcell and cell-matrix interactions and enhance cell-based drug discovery and target validation, vascular constructs to study contractile responses, and myocardial constructs for studying drug toxicities and responses to tissue injury) [13,13a,13b]. The innovative fabrication of materials and the development of sophisticated methods to repair or regenerate damaged or diseased tissues and to create entire organ replacements requires integration of a diverse array of basic scientific principles and enabling technologies. Thus, tissue engineering requires an understanding of relationships of structure to function in normal and pathological tissues