BACKGROUND: We present the synthesis, characterization and initial structure-function analysis of a new class of bioactive agent that allows the application of techniques from colloid science to biological surfaces. Stable colloidal suspensions can be generated by immobilizing a dense brush of soluble polymer at the colloidal surface, creating a zone protected against the adhesion of approaching particles, a phenomenon termed polymeric steric stabilization. This is often accomplished for aqueous colloidal dispersions using adsorbing block copolymers. We demonstrate that water-soluble block copolymers can be designed to adsorb onto heterogeneous biological surfaces and block cell-cell and cell-surface adhesion, using polymer compositions and architectures that are quite different from surfactants used for stabilizing nonbiological colloidal dispersions. RESULTS: Comb copolymers were synthesized having polycationic backbones (poly-L-lysine, PLL), serving as the anchor for binding to the net negatively charged biological surfaces, grafted with water-soluble polynonionic chains (polyethylene glycol, PEG), to block biological recognition, producing PLL-graft-PEG copolymers. Specific copolymers were found to sterically stabilize red blood cells from lectin-induced hemagglutination and fibroblasts from adhesion to fibronectin-coated surfaces. The polymer design principles, which appear to be unique for adsorption to heterogeneous biological surfaces, require the use of very high molecular weight comb copolymers, perhaps because anionic sites are non-uniformly distributed on biological surfaces, and the ability of larger copolymers to span between highly anionic sites. CONCLUSIONS: Water-soluble copolymers were produced that can block recognition at biological surfaces, on the basis of nonspecific physicochemical phenomena rather than specific biochemical interactions. [on SciFinder (R)]