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Schindeler A.,Orthopaedic Research and Biotechnology Unit | Birke O.,Orthopaedic Research and Biotechnology Unit | Yu N.Y.C.,Orthopaedic Research and Biotechnology Unit | Morse A.,Orthopaedic Research and Biotechnology Unit | And 3 more authors.
Journal of Bone and Joint Surgery - Series B | Year: 2011

Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair. Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1+/-) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 ?g rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection. When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1 +/- mice remained ununited at three weeks compared with 7% of controls (p < 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p < 0.07). These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthoris of the tibia and NF1. ©2011 British Editorial Society of Bone and Joint Surgery.

Ravarian R.,University of Sydney | Zhong X.,University of Sydney | Barbeck M.,Johannes Gutenberg University Mainz | Ghanaati S.,Johannes Gutenberg University Mainz | And 7 more authors.
ACS Nano | Year: 2013

Bioglasses are favorable biomaterials for bone tissue engineering; however, their applications are limited due to their brittleness. In addition, the early failure in the interface is a common problem of composites of bioglass and a polymer with high mechanical strength. This effect is due to the phase separation, nonhomogeneous mixture, nonuniform mechanical strength, and different degradation properties of two compounds. To address these issues, in this study a nanoscale interaction between poly(methyl methacrylate) (PMMA) and bioactive glass was formed via silane coupling agent (3-trimethoxysilyl)propyl methacrylate (MPMA). A monolith was produced at optimum composition from this hybrid by the sol-gel method at 50 C with a rapid gelation time (<50 min) that possessed superior physicochemical properties compared to pure bioglass and physical mixture. For instance, the Young's modulus of bioglass was decreased 40-fold and the dissolution rate of silica was retarded 1.5-fold by integration of PMMA. Prolonged dissolution of silica fosters bone integration due to the continuous dissolution of bioactive silica. The primary osteoblast cells were well anchored and cell migration was observed on the surface of the hybrid. The in vivo studies in mice demonstrated that the integrity of the hybrids was maintained in subcutaneous implantation. They induced mainly a mononuclear phagocytic tissue reaction with a low level of inflammation, while bioglass provoked a tissue reaction with TRAP-positive multinucleated giant cells. These results demonstrated that the presence of a nanoscale interaction between bioglass and PMMA affects the properties of bioglass and broadens its potential applications for bone replacement. © 2013 American Chemical Society.

Murphy C.M.,Orthopaedic Research and Biotechnology Unit | O'Brien F.J.,Royal College of Surgeons in Ireland | Little D.G.,Orthopaedic Research and Biotechnology Unit | Little D.G.,University of Sydney | And 2 more authors.
European Cells and Materials | Year: 2013

Bone tissue engineering has emerged as one of the leading fields in tissue engineering and regenerative medicine. The success of bone tissue engineering relies on understanding the interplay between progenitor cells, regulatory signals, and the biomaterials/scaffolds used to deliver them - otherwise known as the tissue engineering triad. This review will discuss the roles of these fundamental components with a specific focus on the interaction between cell behaviour and scaffold structural properties. In terms of scaffold architecture, recent work has shown that pore size can affect both cell attachment and cellular invasion. Moreover, different materials can exert different biomechanical forces, which can profoundly affect cellular differentiation and migration in a cell type specific manner. Understanding these interactions will be critical for enhancing the progress of bone tissue engineering towards clinical applications.

Cheng T.L.,Orthopaedic Research and Biotechnology Unit | Cheng T.L.,University of Sydney | Murphy C.M.,Orthopaedic Research and Biotechnology Unit | Cantrill L.C.,Kids Research Institute | And 6 more authors.
International Orthopaedics | Year: 2014

Purpose: Legg-Calve-Perthes disease is a paediatric condition encompassing idiopathic osteonecrosis of the femoral head (ONFH). Preventing collapse and the need for subsequent joint replacement remains the major goal of clinical management. This exploratory study utilises a porcine model of surgically induced ONFH. Methods: rhBMP-2 with and without zoledronic acid (ZA) was delivered by intra-osseous injection in the phase-transitioning sucrose acetate isobutyrate (SAIB) in an attempt to prevent femoral head collapse. Epiphyseal quotient (EQ) at eight weeks post-surgery was the primary outcome measure. Heterotopic ossification in the joint capsule and bisphosphonate retention in the femoral head were key secondary outcomes. Results: Femoral heads with ONFH and no treatment all collapsed (3/3, EQ<0.4, P<0.05 compared to no ONFH). Local delivery of rhBMP-2/SAIB into the femoral head prevented collapse by EQ measurement one of four samples; however, this specimen still showed evidence of significant collapse. In contrast, the combination of local rhBMP-2 and local ZA prevented collapse in two of four samples. Confocal fluorescence microscopy showed locally dosed bisphosphonate entered and was retained in the femoral head. This group also showed strong Calcein signal, indicating new bone formation. Treatment with rhBMP-2 was associated with a limited amount of heterotrophic ossification in the joint capsules in some specimens. Conclusions: Operators reported SAIB to be an efficient way to deliver rhBMP-2 to the femoral head. These data suggest that rhBMP-2 is ineffective for preventing femoral head collapse without the addition of bisphosphonate. Further research will be required to validate the clinical efficacy of a combined local rhBMP-2/bisphosphonate approach. © 2013 Springer-Verlag.

McDonald M.M.,Orthopaedic Research and Biotechnology Unit | Morse A.,Orthopaedic Research and Biotechnology Unit | Peacock L.,Orthopaedic Research and Biotechnology Unit | Mikulec K.,Orthopaedic Research and Biotechnology Unit | And 4 more authors.
Journal of Orthopaedic Research | Year: 2011

Osteopetrotic patients possess a genetic condition that leads to a deficiency in osteoclast number or function. Patients have a high bone density and suffer from an increased risk of fracture. The lack of normal osteoclast activity has the potential to impede repair by complicating orthopedic fixation and/or by affecting the biology of fracture healing. The naturally occurring incisors absent (ia/ia) rat was adopted as a rodent model of congenital osteopetrosis. A detailed phenotypic analysis of the ia/ia rat indicated that some functional recovery occurred between 7 and 9 weeks. Consequently a fracture repair study was undertaken using 5-week-old rats. Closed femoral fractures were generated in ia/ia rats and control ia/+ and +/+ rats using an Einhorn apparatus. Fracture healing was examined radiologically and histologically at 1-3 weeks. No difference was seen in bridging between ia/ia and control rats at any time point. The ia/ia rats showed no delay in cartilage removal but showed a significant delay in hard callus remodeling. This is consistent with an essential role for osteoclasts in only the latter stages of endochondral bone repair. This delay in hard callus remodeling was offset by an increase in moment of inertia. Copyright © 2010 Orthopaedic Research Society.

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