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Tissue-engineered constructs (TECs) combining resorbable calcium-based scaffolds and mesenchymal stem cells (MSCs) have the capability to regenerate large bone defects. Inconsistent results have, however, been observed, with a lack of osteoinductivity as a possible cause of failure. This study aimed to evaluate the impact of the addition of low-dose bone morphogenetic protein-2 (BMP-2) to MSC-coral-TECs on the healing of clinically relevant segmental bone defects in sheep. Coral granules were either seeded with autologous MSCs (bone marrow-derived) or loaded with BMP-2. A 25-mm-long metatarsal bone defect was created and stabilized with a plate in 18 sheep. Defects were filled with one of the following TECs: (i) BMP (n = 5); (ii) MSC (n = 7); or (iii) MSC-BMP (n = 6). Radiographic follow-up was performed until animal sacrifice at 4 months. Bone formation and scaffold resorption were assessed by micro-CT and histological analysis. Bone union with nearly complete scaffold resorption was observed in 1/5, 2/7, and 3/6 animals, when BMP-, MSC-, and MSC-BMP-TECs were implanted, respectively. The amount of newly formed bone was not statistically different between groups: 1074 mm 3 [970-2478 mm 3 ], 1155 mm 3 [970-2595 mm 3 ], and 2343 mm 3 [931-3276 mm 3 ] for BMP-, MSC-, and MSC-BMP-TECs, respectively. Increased scaffold resorption rate using BMP-TECs was the only potential side effect observed. In conclusion, although the dual delivery of MSCs and BMP-2 onto a coral scaffold further increased bone formation and bone union when compared to single treatment, results were non-significant. Only 50% of the defects healed, demonstrating the need for further refinement of this strategy before clinical use. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2637-2645, 2017., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)