Table 4.

General characteristics and the outcomes of the cell (in vitro) studies included in this review. DM, diabetes mellitus; BMSCs, bone marrow derived stem cells; RT-PCR, real-time polymerase chain reaction; BMP, bone morphogenic protein; ALP, alkaline phosphatase; histo, histology; UV, ultraviolet; Ti, titanium.

Study	Methodology	Cell line used	Metformin concentration	Variables assessed	General outcomes
Lin et al 2020 [33]	Cells from animal models on Ti samples for in vitro experiments	Rat BMSC	50 µM	Autophagy markers (LC3), ROS, production, senescence proteins (P16, P21, and P53), and osteogenic differentiation markers (Runx2, OCN, and ALP)	MET had osteogenic, anti-aging, antioxidative and pro-autophagic effects.
Hashemi et al 2020 [34]	Ti implants coated with TiO2 nanotubes coated with chitosan releasing MET. Cells cultured on untreated Ti, anodized Ti and anodized Ti coated with MET-chitosan samples.	Rat BMSC	N/A	Metformin release (UV spectrometry), ALP activity and expression, type I collagen expression	MET-chitosan coated implants had a sustained release of MET. MET promoted pro-osteogenic effect.
Sun et al 2021 [30]	BMSCs derived from the alveolar bone particles acquired from the implant bed of normal and DM2 patients.	Human BMSC from diabetic and healthy patients	DM group: 0, 100, 200, 300, 400, and 500 µM Healthy group: (0, 50, and 100 µM	ALP detection, alizarin red staining, RT-PCR and Western blotting (anti-p-AMPK, AMPK, BMP-2, Smad1, Runx-2	MET had a dose dependent positive effect on osteogenesis when <200 µM but decreased osteogenesis when >200 µM. MET had pro-osteogenic effect on BMSCs from normal and DM2 individuals.