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Implantation of engineered cartilage with soft callus features triggers remodeling to bone tissue via endochondral bone regeneration (EBR). Thus far, EBR has not progressed to the level of large animals on the axis of clinical translation. In the present study, we aimed to establish the feasibility of EBR for a critical‐sized defect in a large animal model. To achieve this goal, we first induced chondrogenesis in goat‐derived multipotent mesenchymal stromal cells (MSCs) by fine‐tuning the cellular differentiation process. Afterwards, two biomaterials consisting of predominantly extracellular cartilage matrix, were achieved through a unique devitalization process. Thus, off‐the‐shelf constructs were engineered that recapitulate different stages of the transient cartilaginous soft callus template in EBR. To evaluate bone regeneration, we implanted the materials in an adapted bilateral iliac crest defect model in goats, featuring a novel titanium star‐shaped spacer. Both soft callus mimetic biomaterials, were compared to negative controls (empty defect or fibrin carrier) and to the current clinical gold standard treatment, autograft bone. After 3 months, the group with the more advanced differentiation stage showed remarkable regenerative capacity, even reaching comparable amounts of bone regeneration as the autograft group. In contrast, while the biomaterial mimicking the earlier stages of chondrogenesis showed improved regeneration compared to the negative controls, this was subpar compared to the more advanced material. Concluding, endochondral bone regeneration is attainable in large animals with a soft callus mimetic material that leads to fast conversion into centimeter‐scale bone, which prospects successful implementation in the human clinics.This article is protected by copyright. All rights reserved

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