Development of a growth factor delivery system

Kirby, Giles T.S. (2014) Development of a growth factor delivery system. PhD thesis, University of Nottingham.

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Abstract

Bone repair is not always a spontaneous process. In some cases, intervention is required. This can involve the use of autograft but requires donor tissue. As a consequence there is a potential lack of material and donor site morbidity. Current alternatives are limited. There is a need for synthetic alternatives with a similar efficacy to autograft. Growth factors are currently being explored to address this need. A limiting factor to growth factor approaches are safety concerns and high costs. Both these problems stem from the fact that growth factors have short in vivo half lives and are administered at supraphysiological levels to maximise the duration of effect. There is a strong need for a growth factor delivery system that can maintain therapeutic doses and restrict administration to a specific location. This is currently limited by the fragile nature of growth factors.

Microparticles were utilised. Microparticles were formed from poly(DL-lactic-coglycolic acid) with a poly(ethylene glycol) based plasticiser. This provided a method to modulate protein release based on the specific polymer formulation. Protein release was assessed with a model protein. The biological activities of released growth factors were assessed. Microparticles were fabricated for the delivery of vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and bone morphogenetic protein-2 (BMP-2) for release at time points conducive with osteogenic regeneration. A method was developed and validated to combine these microparticles with a suitable scaffold material. These composite scaffolds were developed with the intention of assessing controlled release of growth factors in a bone segmental defect.

A method to fabricate microparticles with consistent size distributions and morphologies was developed. Formulations were tailored such that protein release from microparrticles could be from 2 days to 30 days. The biological activity of the released model protein was verified, as was the biological activity of released BMP-2. A method was devised to combine microparticles with a scaffold suitable for osteogenic regeneration of a segmental defect. This composite scaffold maintained a high level of porosity making it suitable for tissue ingress and growth factor diffusion.

This study addresses key limitations to growth factor therapies. The sustained release of growth factors has the potential to mitigate dose-induced toxic effects as well as maintain therapeutic concentrations for longer periods. The nature of the delivery system delivers localised growth factors minimising the risk of systemic dosing leading to adverse reactions. This microparticle technology has potential in developmental research research as well as clinical therapies.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Shakesheff, K.M.
Rose, F.
Keywords: growth factor, growth factor delivery system, tissue engineering, bone growth
Subjects: Q Science > QP Physiology > QP501 Animal biochemistry
R Medicine > R Medicine (General) > R855 Medical technology. Biomedical engineering. Electronics
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 14123
Depositing User: EP, Services
Date Deposited: 20 Jan 2015 14:14
Last Modified: 14 Sep 2016 09:02
URI: http://eprints.nottingham.ac.uk/id/eprint/14123

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