Christabella AdineKiaw K. NgSasitorn RungarunlertGlauco R. SouzaJoão N. FerreiraNational University of Singapore, Faculty of DentistryChulalongkorn UniversityUniversity of Texas Health Science Center at HoustonNational Institute of Dental and Craniofacial ResearchMahidol UniversityNano3D Biosciences2019-08-232019-08-232018-10-01Biomaterials. Vol.180, (2018), 52-6618785905014296122-s2.0-85049860642https://repository.li.mahidol.ac.th/handle/20.500.14594/45048© 2018 Elsevier Ltd Current saliva-based stimulation therapies for radiotherapy-induced xerostomia are not fully effective due to the presence of damaged secretory epithelia and nerves in the salivary gland (SG). Hence, three-dimensional bio-engineered organoids are essential to regenerate the damaged SG. Herein, a recently validated three-dimensional (3D) biofabrication system, the magnetic 3D bioprinting (M3DB), is tested to generate innervated secretory epithelial organoids from a neural crest-derived mesenchymal stem cell, the human dental pulp stem cell (hDPSC). Cells are tagged with magnetic nanoparticles (MNP) and spatially arranged with magnet dots to generate 3D spheroids. Next, a SG epithelial differentiation stage was completed with fibroblast growth factor 10 (4–400 ng/ml) to recapitulate SG epithelial morphogenesis and neurogenesis. The SG organoids were then transplanted into ex vivo model to evaluate their epithelial growth and innervation. M3DB-formed spheroids exhibited both high cell viability rate (>90%) and stable ATP intracellular activity compared to MNP-free spheroids. After differentiation, spheroids expressed SG epithelial compartments including secretory epithelial, ductal, myoepithelial, and neuronal. Fabricated organoids also produced salivary α-amylase upon FGF10 stimulation, and intracellular calcium mobilization and trans-epithelial resistance was elicited upon neurostimulation with different neurotransmitters. After transplantation, the SG-like organoids significantly stimulated epithelial and neuronal growth in damaged SG. It is the first time bio-functional innervated SG-like organoids are bioprinted. Thus, this is an important step towards SG regeneration and the treatment of radiotherapy-induced xerostomia.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyChemical EngineeringEngineeringMaterials ScienceArticleSCOPUS10.1016/j.biomaterials.2018.06.011