The repair of bone defects and fracture non-unions remain a challenge for clinicians. Current materials have limitations regarding quality, availability and there are long-term complications. Alternative graft materials, often in combination with growth factors have been investigated, but, poor retention of growth factors has lead to the clinical use of high doses and/or frequent injections, putting the patient at risk of adverse effects. The aim was to develop and evaluate a controlled bone morphogenetic protein-2 (BMP-2) delivery system based on poly(lactide-co-glycolide) (PLGA) that would improve current therapies by controlling the dose and localisation of BMP-2 at the treatment site as well as providing a biodegradable scaffold to support the newly formed tissue. Reproducible procedures to manufacture spherical PLGA microparticles of defined sizes within a 1-100 µm range were developed. Lysozyme was used to model rhBMP-2 and it was successfully encapsulated with human serum albumin into PLGA microparticles with high entrapment efficiency and retained its activity upon subsequent release. Release rate was manipulated by the use of a PLGA-PEG-PLGA triblock copolymer and resulted in a number of distinctly different but reproducible cumulative release curves which were applicable to the delivery of different growth factors to mimic in-vivo kinetics. A sustained release profile over one month was chosen for rhBMP-2 delivery and it was shown to remain active upon release demonstrated by up-regulation of alkaline phosphate expression in murine C2C12 myoblast cells and human mesenchymal stem cells. It also induced murine primary calvarial cells to produce a mineralised matrix and caused localised ossification in the epiphysis of an embryonic chick femur. This work has developed a robust, novel method of tailoring protein release and applied it to rhBMP-2. The technology could be transferred to different growth factors and the regeneration of different tissues.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:594731 |
| Date | January 2013 |
| Creators | Cox, Helen Celia |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/13881/ |
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