Summary: The induction of limb repair in adult vertebrates is a pressing, unsolved problem. Here, we characterize the effects of an integrated device that delivers drugs to severed hindlimbs of adult Xenopus laevis, which normally regenerate cartilaginous spikes after amputation. A wearable bioreactor containing a silk protein-based hydrogel that delivered progesterone to the wound site immediately after hindlimb amputation for only 24 hr induced the regeneration of paddle-like structures in adult frogs. Molecular markers, morphometric analysis, X-ray imaging, immunofluorescence, and behavioral assays were used to characterize the differences between the paddle-like structures of successful regenerates and hypomorphic spikes that grew in untreated animals. Our experiments establish a model for testing therapeutic cocktails in vertebrate hindlimb regeneration, identify pro-regenerative activities of progesterone-containing bioreactors, and provide proof of principle of brief use of integrated device-based delivery of small-molecule drugs as a viable strategy to induce and maintain a long-term regenerative response. : The complexity of vertebrate limbs drives the search for regenerative treatments that trigger endogenous processes of repair. Herrera-Rincon et al. show that a wearable bioreactor containing progesterone, applied for only 24 hr, induces months of regenerative growth and patterning of amputated hindlimbs in the frog Xenopus laevis. Keywords: silk, hydrogel device, spike, frog, bioelectricity, regeneration, Xenopus, limb, bioreactor