To provide on-demand therapeutics to diseased site where local and intermittent drug delivery was desirable, temperature-responsive polyurethane (TRPU) which enabled rapid, reproducible and tunable on-off switching release of incorporated drugs was successfully prepared. Differential scanning calorimetric analysis revealed that the TRPU synthesized in this study exhibited segmented structure with partially-miscible fixed phase and reversible phase, which favorably imparted the TRPU a physiologically-tolerable switching temperature at 44 degrees C. Positron annihilation lifetime spectroscopy demonstrated that, as the TRPU underwent sharp phase transition-upon heating through 44 degrees C. the free volume size and fraction within the polymeric matrix expanded dramatically. Based on such discontinuous free volume change, the diffusion of incorporated antibiotic (sulfamethoxazole) and anticancer drug (paclitaxel) from TRPU membrane could be switched off below normal physiological temperature (37 degrees C) while switched on by heating to 44 degrees C. resulting in high on-off ratios. In addition, the TRPU membrane could be thermally-switched on and off rapidly, within less than 5 min after temperature variation, and reproducibly, over four cycles of temperature oscillation between 37 degrees C and 44 degrees C. Furthermore, the amount of drug released during each on state was found to be proportional to the duration of heating. In cell culture assays, the TRPU membrane exhibited no cytotoxicity towards C2C12 myoblasts, 3T3 fibroblasts, Me-T mesothelials and J.1774 macrophages. Compared with ordinary biomedical polyurethane elastomer that delivered drugs at almost constant rate regardless of temperature variation, the TRPU prepared in this study showed great potential for developing biomedical implant which could provide temperature-modulated therapeutics to diseased site. (C) 2011 Elsevier Ltd. All rights reserved.