Abstract
Coronary artery disease and stroke are leading causes of mortality in Europe, resulting in aloss of function of the affected tissue. One of the challenges is to restore the myocardium
tissue functionality using growth-factors mimicking peptides to stimulate the development
of pre-existing blood vessels to enhance tissue regeneration and ensure tissue viability. In
this research, hyperbranched peptides based on poly (ɛ-lysine) (i.e. dendrons) of different
branching generations (Gx) were used as protein scaffolds to present, at their uppermost
branching generation, peptide analogues for key growth factors such as the Angiopoietin-1
(Ang-1), the Vascular Endothelial growth factor (VEGF) or the Platelet Derived growth
factor (PDGF-BB). The resulting dendritic angiogenic peptides have been designed
specifically to target myocardial ischemic tissue starting from a molecular root [diphenilalanine
(FF)] capable of being retained for longer times within the target tissue by
interacting with the extracellular matrix (ECM) through hydrophobic interactions and
being decorated with the specific angiogenic bioactive peptide analogues capable of
inducing a precise biological response in targeting cells.
Synthesis of the dendritic angiogenic peptides was performed using an established solid
phase method by a manual method and characterised by analytical HPLC, Mass
Spectrometry and FT-IR. The angiogenic potential of dendritic angiogenic peptides has
been evaluated by a 2D in vitro model where the human umbilical vein endothelial cells
(HUVECs) were spiked with the soluble linear and dendritic analogues resulting in an
endothelial sprouting. Successively, dendritic angiogenic peptides have been used as
functionalisation molecules for collagen type I engineered as either injectable biomaterials
(beads) or cardiac patches (scaffolds). The potential of these novel synthesised molecules
in inducing angiogenesis in vitro when covalently grafted to the biomaterial surfaces also
showed an angiogenic potential demonstrating that the bioactivity is not confined to their
soluble form. However, their bioactivity in both soluble and grafted form was shown to
depend on the molecular branching of the dendron and relative availability of the bioactive
sequences. Indeed, the present study for the first time unveils a novel biomaterial approach
to stimulate angiogenesis through nano-structured biomaterials and emphasise the need for
a finely spaced presentation of the relevant peptide sequence to obtain established
endothelial sprouting.
| Date of Award | Jan 2018 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Matteo Santin (Supervisor) |