JOURNAL OF CELLULAR PHYSIOLOGY 199:174–180 (2004) REVIEW ARTICLE From Cell–ECM Interactions to Tissue Engineering FRANCESCO ROSSO,* ANTONIO GIORDANO, MANLIO BARBARISI, AND ALFONSO BARBARISI IX Division of General Surgery and Applied Biotechnology, Department of Anaesthesological, Surgical and Emergency Sciences, Second University of Naples, Italy The extracellular matrix (ECM) consists of a complex mixture of structural and functional macromolecules and serves an important role in tissue and organ morphogenesis and in the maintenance of cell and tissue structure and function. The great diversity observed in the morphology and composition of the ECM contributes enormously to the properties and function of each organ and tissue. The ECM is also important during growth, development, and wound repair: its own dynamic composition acts as a reservoir for soluble signaling molecules and mediates signals from other sources to migrating, proliferating, and differentiating cells. Approaches to tissue engineering center on the need to provide signals to cell populations to promote cell proliferation and differentiation. These ‘‘external signals’’ are generated from growth factors, cell–ECM, and cell–cell interactions, as well as from physical-chemical and mechanical stimuli. This review considers recent advances in knowledge about cell–ECM interactions. A description of the main ECM molecules and cellular receptors with particular care to integrins and their role in stimulation of specific types of signal transduction pathways is also explained. The general principles of biomaterial design for tissue engineering are considered, with same examples. J. Cell. Physiol. 199: 174 – 180, 2004. ß 2003 Wiley-Liss, Inc. GENERAL OVERVIEW The main goal of tissue engineering is the reconstruc- tion of living tissues to be used for the replacement of damaged or lost tissues/organs of living organisms. To achieve this, it is necessary to combine the use of cell together with natural or synthetic scaffolds in or onto which cells must develop, organize, and behave as if they are in their native tissue. Therefore, cells must receive signals from the environment to carry out in an orderly way proliferation and differentiation programs finalized to tissue/organ formation (Abatangelo et al., 2001). With regard to these biological process cells need a continuous flow of signals from the surrounding extra- cellular environment that allow for specific genetic program fulfillment. It is tempting to generalize that in all tissues cells live in contact with matrices or scaffolds. Since the early developmental phases, embry- onic cells produce their own extracellular scaffolds, by secreting many types of molecules in the surrounding space, according to a well defined program of differ- entiation (Adams and Watt, 1993; Vaino and Muller, 1997). The different spatial organization of these secreted molecules gives rise to a great variety of natural scaffolds in which cells continue to proliferate and to organize themselves in order to build tissues and to accomplish all their natural functions. The under- standing of cell differentiation and functions means the understanding of cell–cell and cell–extracellular matrix (ECM) communication mechanisms. In this respect, if one looks considering the complexity of tissue ECM components, it is not surprising to find the same great variety and complexity of existing interactions between cells and ECM. Bearing these basic considera- tions in mind, our efforts in trying in vitro tissue reconstruction must be driven toward the exact knowl- edge of cell function on the one hand, and, on the other hand, toward the knowledge of interactions and signals that cells must receive from the environment to behave as in natural tissues (Abatangelo et al., 2001). We know that ECM plays an instructive role for cellular activities and that the cell surface contains receptors to respond to extracellular signals. As soon as ligand – receptor interaction is established, the biochem- ical machinery involved in the control of gene expression starts. ECM COMPOSITION The ECM is composed of a great variety of molecules and includes collagen family, elastic fibers, glycosoami- noglycans (GAG) and proteoglycans, and adhesive glycoproteins. The different combination, immobi- lization, and spatial organization of these secreted ß 2003 WILEY-LISS, INC. *Correspondence to: Francesco Rosso, Department of Anaesthe- sological, Surgical and Emergency Sciences, Second University of Naples, Italy, Piazza Miraglia, 1–80138-Naples, Italy. E-mail: francesco.rosso@unina2.it Received 10 August 2003; Accepted 13 August 2003 DOI: 10.1002/jcp.10471