Localized insulin-like growth factor I delivery to enhance new bone formation.
Insulin-like growth factor I (IGF I) exerts an important role during skeletal growth and bone formation. Therefore, its localized delivery appears attractive for the treatment of bone defects. To prolong IGF I delivery, we entrapped the protein into biodegradable poly(lactide-co-glycolide) microspheres (PLGA MS) and evaluated the potential of this delivery system for new bone formation in two defect models of ovine long bones, i.e., a 8-mm methaphyseal drill hole and a 10-mm segmental tibia defect. Administration of 100 microg of IGF I in PLGA MS resulted in new bone formation within 3 weeks in the drill hole and bridging of the segmental defect within 8 weeks. The observed increase of 12% newly formed bone in the drill hole defect after 3 weeks was substantial, compared to the measured morphometric bone-to-total area ratio of 31% bone in normal cancellous bone. Bone regeneration was further explored by measuring gene expression of typical markers for local mediators and growth factors by real-time polymerase chain reaction. Inflammation was reduced in presence of IGF I and this in vivo observation was corroborated in vitro by quantifying gene expression of inflammatory proteins and by assessing the activation of the NF-kappaB pathway, playing an important role in the regulation of inflammation. Administration of the IGF I delivery system downregulated inflammatory marker gene expression at the site of bone injury, induced new bone formation and reduced bone resorption, and resulted in bridging of 10-mm segmental tibial defects within 8 weeks.
Meinel
Lorenz
L
Institute of Pharmaceutical Sciences, Drug Formulation and Delivery Group, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Zoidis
Evangelos
E
Zapf
Jürgen
J
Hassa
Paulo
P
Hottiger
Michael O
MO
Auer
Jörg A
JA
Schneider
Rebecca
R
Gander
Bruno
B
Luginbuehl
Vera
V
Bettschart-Wolfisberger
Regula
R
Illi
Oscar E
OE
Merkle
Hans P
HP
von Rechenberg
Brigitte
B
D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016503:Drug Delivery Systems; D005260:Female; D017102:Fracture Healing / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008863:Microspheres; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage; D012756:Sheep
D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D016328:NF-kappa B; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases