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Amputation of the digit tip within the terminal phalangeal bone of rodents, monkeys, and humans results in near‐perfect regeneration of bone and surrounding tissues; however, amputations at a more proximal level fail to produce the same regenerative result. Digit regeneration is a coordinated, multifaceted process that incorporates signaling from bioactive growth factors both in the tissue matrix and from several different cell populations. To elucidate the mechanisms involved in bone regeneration we developed a novel multi‐tissue slice‐culture model that regenerates bone ex vivo via direct ossification. Our study provides an integrated multi‐tissue system for bone and digit regeneration and allows us to circumvent experimental limitations that exist in vivo. We used this slice‐culture model to evaluate the influence of oxygen on regenerating bone. Micro–computed tomography (µCT) and …