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Eshaghali Saberi,1 Narges Farhad-Mollashahi,1 Fereydoon Sargolzaei Aval,2,3 Mersad Saberi41Oral and Dental Diseases Research Center, Department of Endodontics, Faculty of Dentistry, Zahedan University of Medical Sciences, Zahedan, Iran; 2Cellular and Molecular Research Center, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran; 3Department of Anatomical, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran; 4General Dentist, Zahedan, IranIntroduction: Clinical applications of bioactive materials are increasing in biomedical tissue engineering. This study sought to assess the effect of calcium enriched mixture (CEM) cement, Biodentine, mineral trioxide aggregate (MTA), octacalcium phosphate (OCP), and Atlantik on proliferation, odontogenic/osteogenic differentiation, and pro-inflammatory cytokine production by human stem cells of the apical papilla (SCAPs).Materials and methods: Proliferation of SCAPs treated with different biomaterials was evaluated using trypan blue exclusion test and flow cytometry. Differentiation of cells was evaluated using ALP activity, alizarin red staining, and RT-PCR. The expression of genes of pro-inflammatory cytokines was also evaluated using RT-PCR.Results: The SCAPs treated with biomaterials showed significantly higher proliferation, increased ALP activity, higher number of calcified nodules, and up-regulation of genes related to odontogenic/osteogenic markers compared to the control group. The expression of pro-inflammatory cytokines increased in all groups compared to the control group.Conclusion: The tested biomaterials could induce odontogenic/osteogenic differentiation in SCAPs. MTA had a greater potential for induction of differentiation of SCAPs to odontoblast-like cells while OCP had higher potential to induce differentiation of SCAPs to osteoblast-like cells (MTA↔ BD↔ CEM↔ Atlantik↔ OCP).Keywords: apical papilla, biomaterials, odontogenic differentiation, stem cells