In vivo local co-delivery of recombinant human bone morphogenetic protein-7 and pamidronate via poly-D, L-lactic acid
1 Department of Orthopaedic Research & Biotechnology, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia
2 School of Aerospace, Mechanical and Mechatronic Engineering, J07 University of Sydney, NSW 2006, Australia
3 Discipline of Paediatrics and Child Health, Faculty of Medicine, A27 University of Sydney, NSW 2006, Australia
4 Osteoporosis and Bone Biology Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
Abstract
The effects of bone anabolic agents such as bone morphogenetic proteins (BMPs) have the potential to be augmented by co-treatment with an anti-catabolic such as a bisphosphonate. We hypothesised that the effects of bisphosphonates on BMP-induced bone anabolism would be dose dependent, and we aimed to test this in a small animal model. Agents were delivered locally using a biodegradable poly-d, l-lactic-acid (PDLLA) polymer delivery system. Recombinant human BMP-7 (25 µg) was tested with a range of doses of the bisphosphonate pamidronate (0.02 mg, 0.2 mg and 2 mg local PAM; 0.3 mg/kg and 3 mg/kg thrice-weekly systemic PAM) versus BMP-7 alone. Polymer pellets were surgically implanted in the hind limbs of female C57BL6/J mice (8-10 week) and ectopic bone nodules were harvested at 3 and 8 weeks post-operatively. At 3 weeks, local low dose PAM (0.02 mg) induced a 102% increase in rhBMP-7 induced bone volume (p<0.01) as measured by miroCT, and this was comparable to systemic PAM (0.3 mg/kg thrice-weekly). In contrast, local high dose PAM (2 mg) resulted in a 97% decrease in bone volume (p<0.01). Radiography and histology indicated that the polymer vehicle was still largely present at 8 weeks indicating inefficient biodegradation. This is the first study to validate the utility of local co-delivery of BMP/bisphosphonate via biodegradable polymer and supports the continued refinement of more advanced bioresorbable delivery systems for clinical applications.
Keywords
- Anabolism
- catabolism
- bone tissue engineering
- bone morphogenetic protein (BMP)
- bisphosphonate
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