title: Impact of IGF-I release kinetics on bone healing: a preliminary study in sheep.
abstract: Spatiotemporal release of growth factors from a delivery device can profoundly affect the efficacy of bone growth induction. Here, we report on a delivery platform based on the encapsulation of insulin-like growth factor I (IGF-I) in different poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) microsphere (MS) formulations to control IGF-I release kinetics. In vitro IGF-I release profiles generally exhibited an initial burst (14-36% of total IGF-I content), which was followed by a more or less pronounced dormant phase with little release (2 to 34 days), and finally, a third phase of re-increased IGF-I release. The osteoinductive potential of these different IGF-I PL(G)A MS formulations was tested in studies using 8-mm metaphyseal drill hole bone defects in sheep. Histomorphometric analysis at 3 and 6 weeks after surgery showed that new bone formation was improved in the defects locally treated with IGF-I PL(G)A MS (n=5) as compared to defects filled with IGF-I-free PL(G)A MS (n=4). The extent of new bone formation was affected by the particular release kinetics, although a definitive relationship was not evident. Local administration of IGF-I resulted in down-regulation of inflammatory marker genes in all IGF-I treated defects. The over-expression of growth factor genes in response to IGF-I delivery was restricted to formulations that produced osteogenic responses. These experiments demonstrate the osteoinductive potential of sustained IGF-I delivery and show the importance of delivery kinetics for successful IGF-I-based therapies.
authors: Institute of Pharmaceutical Sciences, Drug Formulation & Delivery Group, Swiss Federal Institute of Technology Zurich, Switzerland. vera.luginbuehl@zhaw.ch.
authors: Vera
authors: V
authors: Luginbuehl
authors: Evangelos
authors: E
authors: Zoidis
authors: Lorenz
authors: L
authors: Meinel
authors: Brigitte
authors: B
authors: von Rechenberg
authors: Bruno
authors: B
authors: Gander
authors: Hans P
authors: HP
authors: Merkle
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000502:physiology; D045744:Cell Line, Tumor; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004343:Drug Implants; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D008863:Microspheres; D010012:Osteogenesis / Q000187:drug effects; D011091:Polyesters / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011897:Random Allocation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D034561:Sheep, Domestic; D012995:Solubility; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D004343:Drug Implants; D006133:Growth Substances; C583557:IGF1 protein, human; D018836:Inflammation Mediators; D011091:Polyesters; D011994:Recombinant Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D007334:Insulin-Like Growth Factor I
keywords: Bone healing; Gene expression; Insulin-like growth factor I (IGF-I); Osteoinduction; PLGA microspheres; Release kinetics