Highly-efficient morphogens for guided angiogenesis

  • Maria Verdenelli

    Student thesis: Doctoral Thesis


    Coronary artery disease and stroke are leading causes of mortality in Europe, resulting in a
    loss 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 AwardJan 2018
    Original languageEnglish
    Awarding Institution
    • University of Brighton
    SupervisorMatteo Santin (Supervisor)

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