Conference Paper Early Osteogenic Differentiation of Human Mesenchymal Stem Cells on SLA and modified–SLA Implant Surfaces: A Systematic Review. Siddharth Shanbhag Siddharth Shanbhag Siddharth Shanbhag Andreas Stavropoulos Andreas Stavropoulos Andreas Stavropoulos Conference: ITI World Symposium, At Geneva, Switzerland ABSTRACT Constant efforts are made to accelerate and enhance the process of osseointegration, for example via topographical or chemical modifications of titanium (Ti) implant surfaces. Among these are the hydrophobic, sand–blasted, acid–etched (SLA®) and hydrophilic, chemically modified–SLA (SLActive®) surfaces. These surfaces reportedly enhance osseointegration by influencing early cell responses in the local environment. Undifferentiated mesenchymal stem/stromal cells (MSCs) are among the first cells to colonize peri-implant regeneration sites. The recruitment, proliferation and osteogenic differentiation (OD) of these cells, especially in early stages, can influence the rate and degree of osseointegration. The aim of this study was to systematically review the available literature on the early OD of MSCs or progenitor cells on SLA and SLActive implant surfaces. Medline was searched for related literature. In vitro studies reporting the behaviour of human mesenchymal “stem”, “stromal” or “progenitor” cells cultured on commercial SLA and/or SLActive surfaces in comparison to unmodified (“smooth”) or other modified surfaces, were assessed based on inclusion/exclusion criteria. Fourteen of 145 search–identified studies were included. Human MSCs derived from bone marrow, embryonic palate or periodontal ligament, and progenitor stem cells from alveolar bone were used, mostly in early passages (0–4). Cells were grown on Ti disks with SLA or SLActive surfaces and compared to cells cultured on smooth, hydroxyapatite (HA) coated, plasma–sprayed (TPS), dual acid–etched (DAE), grit–blasted (GB), fluoride–modified (FGB) or magnesium–implanted SLA (Mg–SLA) surfaces. Early osteogenic responses included changes in cell morphology and surface adhesion (1–72 hours), cell proliferation, OD via protein or gene expression, alkaline phosphatase (ALP) activity (1–21 days) and/or in vitro mineralization (7–21 d). A general trend for slower initial (1–24 h) cell response to the SLA and SLActive surfaces was observed, i.e. cells on these surfaces were less flattened, had fewer cytoplasmic extensions (suggestive of slower spreading) and significantly lower absolute numbers (proliferation) than on smooth surfaces. However at later times (3–7 d) there were no significant differences between the different surfaces and in some studies greater proliferation was observed on both SLA surfaces with time. Cells cultured on SLA and SLActive surfaces consistently showed differentiation towards an osteoblastic lineage via early activation of key stem cell signalling pathways (TGFβ–BMP, WNT and Notch). The up–regulation of various osteoblastic and angiogenic genes, transcription factors (e.g. Runx2, Osx) and bone–specific proteins (e.g. osteocalcin, bone sialoprotein, BMPs) were significantly enhanced in these cells, while osteoclastogenic genes (e.g. RANKL) were down–regulated. Enhanced ALP activity, extracellular matrix production and mineralization on both SLA surfaces was observed as early as 1 week. An often significant trend for improved OD and mineralization was observed on the SLActive vs. SLA surface. In some studies a TPS and Mg–SLA surface enhanced OD compared to SLA, while in others OD was equally enhanced on all modified surfaces (SLActive, GB, FGB, DAE and HA). In summary, SLA and SLActive implant surfaces can enhance 1) early differentiation of MSCs and progenitor cells towards an osteoblastic lineage via differential regulation of osteoblastogenic/osteoclastogenic genes and activation of key cell signalling pathways; and 2) early deposition of mineralized collagen matrix (new bone) by the differentiated cells on Ti - suggesting a likely mechanism for improved in vivo osseointegration. A trend for better osteogenic response to the SLActive vs. SLA surface was observed. Further studies are needed to compare these osteogenic responses with other commercial implant surfaces.