Previous efforts attempted to induce limb regeneration in nonregenerative models with the use of electrical stimulation ( 2– 6), tissue-guiding biomaterials ( 7), progenitor cell transplantation ( 8– 10), and the direct up-regulation of key molecular pathways ( 11, 12). Thus, identifying and potentiating the underlying programs that drive limb regrowth would be of great interest to medical and research fields. Moreover, unlike single-purpose mechanoelectrical appendages, developing regenerative methodologies targeting limbs might be instructive in the regeneration of other organs. Despite significant technological advances, clinicians still lack tools to facilitate the recovery or reversal of tissue loss, while prosthetics offer only limited functional restoration of the patient’s own limbs. The prevalence of human limb loss in the United States alone is expected to increase substantially over the next 30 years, affecting 3.6 million individuals per year by 2050 ( 1), leaving diabetics, veterans of war, trauma survivors, and those suffering from peripheral artery disease with limited options in the event of an amputation. The longstanding goal of regenerating whole complex organs has remained elusive despite receiving considerable attention from developmental and regenerative biology. These data demonstrate the successful “kickstarting” of endogenous regenerative pathways in a vertebrate model. RNA sequencing of early tissue buds revealed activation of developmental pathways such as Wnt/β-catenin, TGF-β, hedgehog, and Notch. Regenerated tissues composed of skin, bone, vasculature, and nerves significantly exceeded the complexity and sensorimotor capacities of untreated and control animals’ hypomorphic spikes. laevis hindlimb following a 24-hour exposure to a multidrug, pro-regenerative treatment delivered by a wearable bioreactor. Here, we demonstrate long-term (18 months) regrowth, marked tissue repatterning, and functional restoration of an amputated X. Organisms such as Xenopus laevis-whose limited regenerative capacities in adulthood mirror those of humans-are important models with which to test interventions that can restore form and function. Identifying triggers of innate morphogenetic responses in vivo to induce the growth of healthy patterned tissue would address the needs of millions of patients, from diabetics to victims of trauma. Limb regeneration is a frontier in biomedical science.

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