title: Local application of growth factors (insulin-like growth factor-1 and transforming growth factor-beta1) from a biodegradable poly(D,L-lactide) coating of osteosynthetic implants accelerates fracture healing in rats.
abstract: In vitro and in vivo studies have demonstrated an osteoinductive effect of growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1). However, for therapeutic use in fracture treatment, questions remain with regard to the local application of these proteins. A controlled, local release of growth factors from a biodegradable polylactide coating of osteosynthetic implants may have a stimulating effect on fracture healing. Such implants could stabilize the fracture and their bioactive surface could function simultaneously as a local drug-delivery system. Previous studies have demonstrated the high mechanical stability of an approximately 10-14-microm-thick poly(D,L-lactide) (PDLLA) coating on metallic implants, which can even withstand the process of intramedullary insertion. Following an initial peak, 80% of incorporated growth factors IGF-1 and TGF-beta1 were continuously released within 42 days. The effect of locally applied IGF-1 and TGF-beta1 from a biodegradable PDLLA coating of intramedullary implants on fracture healing was investigated in a rat model. Midshaft fractures of the right tibia of 5-month-old female Sprague-Dawley rats (n = 127) were stabilized with coated vs. uncoated titanium Kirschner wires. X-ray examinations and blood analyses were performed, and body weight and body temperature measurements were taken throughout the experimental period. After 28 and 42 days, respectively, tibiae were dissected for mechanical torsional testing and histomorphometrical analyses. X-rays demonstrated an almost completely consolidated fracture, biomechanical testing showed a significantly higher maximum load and torsional stiffness, and histological and histomorphometric analyses demonstrated progressed remodeling after 28 and 42 days in the group treated with growth factors as compared with controls. Interestingly, the PDLLA coating itself revealed a positive effect on fracture healing even without incorporated growth factors. No systemic changes of serum parameters, including IGF-1 and IGF binding proteins, and no differences in body weight and body temperature were observed within and between groups. These findings suggest that the local application of growth factors from a biodegradable PDLLA coating of osteosynthetic implants accelerates fracture healing significantly without systemic side effects.
authors.affiliation: Department of Trauma and Reconstructive Surgery, Charité, Humboldt University of Berlin, Berlin, Germany. gerhard.schmidmaier@charite.de
authors.forename: G
authors.initials: G
authors.lastname: Schmidmaier
authors.forename: B
authors.initials: B
authors.lastname: Wildemann
authors.forename: H
authors.initials: H
authors.lastname: Bail
authors.forename: M
authors.initials: M
authors.lastname: Lucke
authors.forename: T
authors.initials: T
authors.lastname: Fuchs
authors.forename: A
authors.initials: A
authors.lastname: Stemberger
authors.forename: A
authors.initials: A
authors.lastname: Flyvbjerg
authors.forename: N P
authors.initials: NP
authors.lastname: Haas
authors.forename: M
authors.initials: M
authors.lastname: Raschke
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001696:Biomechanical Phenomena; D001831:Body Temperature; D001835:Body Weight; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology*; D010012:Osteogenesis / Q000187:drug effects*; D019736:Prostheses and Implants; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013978:Tibial Fractures / Q000000981:diagnostic imaging; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001672:Biocompatible Materials; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I