Title:
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Enhancing host cell responses via lipid-functionalisation of orthopaedic titanium
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Total joint replacement surgery is an excellent treatment for arthritis. Unfortunately around
10% of these prostheses will fail due to aseptic loosening and require revision surgery that is
both expensive and less successful for patients. One way of reducing revision surgery could
include steps to enhance human osteoblast (hOB) maturation at biomaterial surfaces by
modifying existing implant materials. The aim of this research therefore was to create a
lipid-functionalised titanium surface that encourages maturation of hOBs, a key event for
successfuI osseo integration.
Lysophosphatidic acid (LPA) refers to a family of structurally-related bioactive lipids. One of
these molecules, oleoyl-LPA, had already been shown to enhance vitamin D3-induced hOB
formation and maturation in vitro. Novel results presented within this thesis indicate that
LPA members and structurally related synthetic lipids exhibit different potencies with regard
to vitamin D3-induced hOB maturation. In summary the finding ofthis thesis indicate that
the synthetic compounds are especially efficacious in securing vitamin D3-induced hOB
maturation.
When developing bioactive titanium surfaces for orthopaedic applications it is important to
examine hOB responses to the selected agent(s) in combination with factors central to
skeletal health. In this thesis, initial studies focused on an important local mediator,
transforming growth factor ~ (TGF~) . In addition research extended to two widely
recognised systemic factors, parathyroid hormone (PTH) and oestradiol. Interestingly TGF~
bolstered the maturation of hOBs to LPA and vitamin D3 via a mechanism that may involve
an autocrine/paracrine platelet-derived growth factor (PDGF) loop. In contrast oestradiol
and parathyroid hormone (PTH) appeared to be without influence on the maturation
responses of hOBs to LPA.
In light of the risk of prosthetic joint infections, it is also important to consider whether any
surface modification promotes or deters the growth of microorganisms. Whilst oleoyl-LPA
lacked appreciable antimicrobial actions, it did not promote bacterial growth. In contrast,
palmitoyl-LPA appeared to have greater antimicrobial activity and may therefore be an
interesting molecule to investigate further in developing multifunctional bone biomaterials
that combine host tissue biocompatibility with an antibacterial surface finish .
In considering titanium surface functionalisation with LPA (or indeed related lipids) the
potential for self-assembly of lipid bi-Iayered structure presented itself as an attractive and
facile means of modification. To this end titanium was initially treated with an
alkanephosphonate (octadecylphosphonic acid) that served as a tethering point for LPA via
tail -tail - hydrophobic interactions akin to the arrangement of phospholipids in cell
membranes. The findings of this thesis support the successful functionalisation oftitanium
using this simple approach . Future research should continue in exploring the stability and
biocompatibility of these novel titanium modifications.
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