Abstract
Bone development and regeneration is associated with the Wnt signaling pathway that, according to literature, can be modulated by lithium ions (Li+). The aim of this study was to evaluate the gene expression profile during peri-implant healing of poly(lactic-co-glycolic acid) (PLGA) implants with incorporated Li+, while PLGA without Li+ was used as control, and a special attention was then paid to the Wnt signaling pathway. The implants were inserted in rat tibia for 7 or 28 days and the gene expression profile was investigated using a genome-wide microarray analysis. The results were verified by qPCR and immunohistochemistry. Histomorphometry was used to evaluate the possible effect of Li+ on bone regeneration. The microarray analysis revealed a large number of significantly differentially regulated genes over time within the two implant groups. The Wnt signaling pathway was significantly affected by Li+, with approximately 34% of all Wnt-related markers regulated over time, compared to 22% for non-Li+ containing (control; Ctrl) implants. Functional cluster analysis indicated skeletal system morphogenesis, cartilage development and condensation as related to Li+. The downstream Wnt target gene, FOSL1, and the extracellular protein-encoding gene, ASPN, were significantly upregulated by Li+ compared with Ctrl. The presence of β-catenin, FOSL1 and ASPN positive cells was confirmed around implants of both groups. Interestingly, a significantly reduced bone area was observed over time around both implant groups. The presence of periostin and calcitonin receptor-positive cells was observed at both time points. This study is to the best of the authors' knowledge the first report evaluating the effect of a local release of Li+ from PLGA at the fracture site. The present study shows that during the current time frame and with the present dose of Li+ in PLGA implants, Li+ is not an enhancer of early bone growth, although it affects the Wnt signaling pathway.
Highlights
Orthopedic and dental implant therapies have evolved into important treatments for deranged joints and lost teeth or to provide fixation of bone in the case of fractures
In addition to providing insights into Wnt signaling during periimplant healing around bone-anchored implants, this study shows that a local release of Li+ at the fracture site can be used to modulate bone cell signaling but needs further optimization in order to induce early bone growth
A similar morphology was observed for the Ctrl samples, with less porosity after 7 days compared to Li+ specimens (Fig. 1F and G, respectively)
Summary
Orthopedic and dental implant therapies have evolved into important treatments for deranged joints and lost teeth or to provide fixation of bone in the case of fractures. PLGA is in clinical use since decades and its biosafety is proven in many medical applications[16,18] It has been used as a carrier for the delivery of osteogenic factors for cell adhesion, differentiation and improved bone regeneration, as pure PLGA implants or in combination with hydroxyapatite (HA) to obtain an improved mechanical strength[19,20,21,22,23]. In addition to providing insights into Wnt signaling during periimplant healing around bone-anchored implants, this study shows that a local release of Li+ at the fracture site can be used to modulate bone cell signaling but needs further optimization in order to induce early bone growth
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