The study presents the possibility to use the 2-hydroxyethyl methacrylate--HEMA copolymer with a comonomer with spiroacetal moiety, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane)-U, as polymer network for loading the indomethacin--INN as drug model, and also, the controlled release evaluation of the prepared bioactive system. The macromolecular compounds were prepared by radical dispersion polymerization in the presence of a pair of surfactants. The use of cyclodextrin as surfactant allowed the building of the host-guest complexes by inclusion of hydrophobic molecules. Also, the cyclodextrin supplemented the hydrogen bonds and the hydrophobic interactions responsible for the stability of the achieved complexes. The copolymers composition and the INN inclusion onto the polymeric matrix were confirmed by FTIR analysis. The porous structure of the lyophilized P(HEMA-U) samples was illustrated by SEM images. The swelling studies evidenced the interdependence between P(HEMA-U) network properties and the spiroacetal moiety amount. Thus, the copolymers presented the increase of the equilibrium swelling degree with pH and temperature. Also, the polymeric matrices manifested dual sensitivity with pH and temperature. The in vitro release of the INN drug from the polymeric network as well as the in vivo experimental studies evidenced the benefit consequence of the spiroacetal compound presence. The clinical observation of the experimental groups does not show any behavioral modifications to suggest a possible toxic effect of these polymeric formulations with and without INN.