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Traumatisms, infections and bone disorders are main causes that affect bone homeostasis and produce damage in bone tissue. Their clinical relevance and increase in the elderly population has promoted intensive research in the area of bone regeneration during the last years. Nevertheless, unsatisfactory results have extended the search for the perfect bone regeneration-promoting platform to the present day. This platform should be highly biocompatible and, ideally, benefit from the intrinsic biopotential of endogenous molecules. Nevertheless, endogenous molecules are prone to lose their activity when submitted to harsh conditions. Therefore, their incorporation into a regenerative platform is very challenging. The authors developed hydrogel scaffolds formed by gellan gum and physically cross-linked by the endogenous polyamine spermidine. The mild preparation conditions permitted the incorporation of other interesting endogenous molecules, including Bone Morphogenetic Protein 2 (BMP-2). Indeed, the effective trans-differentiation of C2C12 cells toward osteoblastic lineage confirmed the release of bioactive BMP-2. After in vivoimplantation in Wistar rats, abundant angiogenesis, mature bone tissue and bone marrow tissue were observed. BMP-2 was also loaded into a commercial scaffold formulation, thus allowing for comparison. Micro-computed tomography and tissue staining confirmed the ability of the studied hydrogel scaffolds to induce the formation of more mature and dense ectopic bone tissue, which remained during a longer period without being reabsorbed when compared with the commercial formulation. These results confirm the potential of the developed hydrogel scaffolds as both innovative growth factor delivery platforms and scaffolds for regenerative medicine applications., info:eu-repo/semantics/publishedVersion