||In mammalian tissues, cells are surrounded by the extracellular matrix (ECM) - a complex network of proteins, glycosaminoglycans (GAGs) and proteoglycans (PGs). The ECM regulates numerous crucial processes such as cell proliferation, differentiation, migrations, and a variety of signaling events. Synthetic extracellular matrices (sECMs) were developed in an attempt to mimic the properties of natural ECMs, specifically for tissue engineering applications. Several sECMs are not commercially available. We compared these materials side by side in a representative array of assays, to test their biological performances and user-friendliness. Our results indicate that the ECM composition and compliance greatly influence cell behavior. Based on these data, we underline the need for a paradigm shift from classical two-dimensional (2D) culturing to the more relevant, in vivo-like three-dimensional (3D) techniques especially for applications directly translatable to clinical applications. Haloacetate-modified hyaluronan (HA) polymers were synthesized and characterized in an effort to provide a greater variety of sECM components. A novel approach was employed that yielded "chemically-reversed," electrophilic HA polymers that could be readily crosslinked with a variety of available nucleophiles. The new haloacetate-modified hyaluronan materials show dose-dependent mild cytotoxic effects and appear promising for adhesion prevention or medical device coating. A novel thiol-modified hyaluronan polymer (HASH) was also synthesized. These biomaterials are not crosslinkable, are well tolerated by cell and shows promising results in a rat arthritis model, by slowing down the disease progression rate. sECMs emerged to be particularly suitable for application such as drug screening. To this end, Extracel ™, a hyaluronan and gelatin-based crosslinked hydrogel was used to examine the effect of alpha-substituted lysophosphatidic acid (LPA) analogs. LPA and its synthesizing enzyme autotaxin (ATX) were associated in numerous studies with aberrant cellular behavior, mostly associated with cancer and tumorigenicity. The compounds tested show cell-line dependent and LPA receptor-specific effect in cell proliferation assays. Further studies that address modulation of cellular invasiveness and metastatic potential are needed for a complete profiling of these chemicals.