The present disclosure relates to novel bis-maleic anhydrides and to the surprising discovery that bis-maleic anhydride cross-linking agents can be used for preservation/fixation of a cell or tissue sample. Various bis-maleic anhydride cross-linking agent scan be used in methods requiring fixation of a cell or tissue sample. These reagents and methods are especially useful in procedures that require that the fixation agent be removed in order to facilitate analysis with other reagents. The inventive reagents and methods make it easier to reliably assay for various proteins, a nucleic acid and the like using analytical methods such as like immunohistochemistry, fluorescence in situ hybridization, RT-PCR, and the like.