title: Gene expression profiling of peri-implant healing of PLGA-Li+ implants suggests an activated Wnt signaling pathway in vivo.
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.
authors.affiliation: Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Thorfve
authors.affiliation: Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; SuMo BIOMATERIALS VINN Excellence Center, Gothenburg, Sweden; Stiftelsen Chalmers Industriteknik, Chalmers Teknikpark, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Bergstrand
authors.affiliation: Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Ekström
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Lindahl
authors.affiliation: Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Thomsen
authors.affiliation: Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; SuMo BIOMATERIALS VINN Excellence Center, Gothenburg, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Larsson
authors.affiliation: Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
authors.forename: Pentti
authors.initials: P
authors.lastname: Tengvall
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects*; D020869:Gene Expression Profiling; D019344:Lactic Acid / Q000737:chemistry*; D008094:Lithium / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013977:Tibia / Q000187:drug effects / Q000502:physiology* / Q000601:surgery / Q000648:ultrastructure; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D051153:Wnt Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008094:Lithium