**12. Tissue engineering using stem cells: can it be avoided?**

It has been asserted that tissue engineering might be the future of endodontics [86]. It is stated in the abstract that pulpal regeneration after tooth injury is not easily accomplished, since the infected pulp is required for tooth extraction or root canal therapy. It is further asserted that an ideal form of therapy might consist of regenerative approaches where diseased or necrotic pulp tissues are removed and replaced with healthy pulp tissue to revitalize the affected tooth. The authors list different techniques, ranging from stem cell therapy, the use of growth factors, pulp implants, implant of 3D cell printed in hydrogels, injectable scaffolds, bioactive materials, the use of co-enzymes, and root canal revascularization. However, despite alleged advantages of the subject approaches, they also suffer major disadvantages like low cell survival, lack of de novo production of pulp, necrosis of reinfected pulp, and lack of vascularity, and requirement for precise root canal fitting.

By determining the cut point of toxicity (i.e., cell death/enhanced apoptosis and lack of proper differentiation induced by the leakage of monomers of endodontic filling materials), it is possible to develop new filling materials without an acute and long term detrimental effect on DPSCs. Hence, the development of a test battery to check the monomers that may diffuse into the root canal, for cytotoxicity and ability to attain proper and functional cell phenotypes (i.e., odontoblasts, neural lattice, and endothelial cells constituting blood vessels) seems mandatory. The present project description aims to define such a test battery using highly sophisticated techniques like proteomics (including phosphoproteomics) and mass cytometry.

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The advantage of using such techniques resides with the fact that extremely few cells may be used in complex arrays of incubation conditions, while still yielding reliable results. The technology described in the present project outline, may also enable the definition of a minimal and sufficient array of variables, which precisely describes a robust test battery to be implemented as a gold standard to be adopted in the development of endodontal biomaterial fillings in the future.
