Novel Growth Factor Delivery Systems from Self-Assembling Peptide (SAP) Hydrogels
Date
2016
Authors
Bruggeman, Kiara Anaya Fay
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Abstract
Growth factors are important signalling molecules in regenerative
medicine and tissue engineering, but their inherent instability,
lasting only minute to hours in vivo, presents an obstacle to
sustained and controlled delivery. This is particularly difficult
to achieve in the brain, where the blood brain barrier (BBB)
prevents systemic delivery. For this reason, much research is
currently directed at incorporating growth factors into
supportive tissue engineering materials that mimic the natural
extracellular matrix (ECM). In this case temporally controlled
and sequential delivery must come from selectively delaying the
release of some growth factors from the material. Here, we aim to
develop novel growth factor delivery systems to provide
temporally controlled growth factor delivery from self-assembling
peptide (SAP) hydrogel materials specifically.
We use minimalist and tissue-specific Fmoc-SAP hydrogels, a novel
class of material designed around biologically recognisable
peptide sequences, engineered to self-assemble at physiological
conditions into supportive nanofibres. We demonstrate the
biocompatibility of three distinct sequences in vivo with cell
grafts into an intact brain, as well as the tissue-specificity of
the materials, with the brain protein laminin derived SAPs
showing superior performance. We also demonstrate their ability
to improve cell graft treatment efficacy in an ischemic brain
injury in rats, showing improved sensorimotor recovery, increased
neuronal differentiation, and reduced cortical atrophy compared
to the unsupported cell graft treatment.
We demonstrate that these materials stabilise growth factors to
provide sustained delivery, with release detected out to 6 weeks.
Sustained delivery of growth factors is a common goal in growth
factor delivery, and here we go beyond that by providing novel
systems for temporally controlled delivery, allowing the
sequential delivery of multiple growth factors required to
achieve their full therapeutic potential. We have successfully
demonstrated systems to provide a short delay of 4 hours, a long
delay of 6 days, and stimuli-responsive control of the delivery
profiles. Covalent attachment of the polysaccharide chitosan to
the growth factor increased physical associations with the SAP
nanofibres, delaying its release by 4 hours. Using emulsion
electrospinning to create polymer nanofibres loaded with growth
factor, we then cut short fibres to mix into the SAP hydrogel.
The polymer provided an additional barrier to diffusion, delaying
the release from the hydrogel by 6 days. Covalent attachment of
growth factor to UV-sensitive nanoparticles allowed for
counter-intuitive control over growth factor delivery, with UV
exposure reducing the growth factor released. We were also able
to use this system to tune the shape of the temporal release
profile to provide a constant dose delivery with no initial
burst. These novel systems demonstrate an improved level of
control of growth factor delivery without sacrificing the tissue
engineering material properties, and represent a significant
contribution to the field of tissue engineering.
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self-assembling peptide, drug delivery, tissue engineering, regenerative medicine, growth factor, controlled release
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