Protein-based Biointerfaces to Control Stem Cell Differentiation - Biointerfaces: Where Material Meets Biology - page 10

and recruitment of different bone cells involved in bone healing, respect-
ively. 58,59 Bone morphogenetic protein (BMP) influences the osteogenic
differentiation of progenitor bone cells, and vascular endothelial growth
factor (VEGF) enhances the formation of functional blood vessels. Recently,
small peptides resembling the functionality of physiologically active proteins
have grown an increasing interest. Therapeutic peptides overcome many
drawbacks of macromolecules, such as long synthesis time, high production
costs, low stability, limited long-term e ciency, or risk of unforeseen side
effects. Small peptides carrying the active site of several growth factors have
already been developed. For example, Tanihara and co-workers found that a
20 amino acid peptide sequence from the 'knuckle' epitope of BMP-2 shows
the biological activity of the full-length BMP-2 protein. 60 Similarly, a VEGF-
mimetic peptide has been synthesized and has shown retaining the bio-
logical activity of VEGF protein. 61 Moreover, several peptides able to inhibit
bone resorption have been synthesized after the identification of osteopro-
tegerin (OPG) and RANKL, important elements in the bone remodeling
pathway. 62
During the last few years orthopedic researchers aiming to regenerate and
repair bone have realized that the appropriate function of engineered bone
substitutes cannot rely on the sole diffusion of nutrients and oxygen. 63 The
lack of a functional vascular network results in the formation of necrotic
cores within the bone substitute. 64,65 Therefore, engineered bone scaffolds
with clinically relevant sizes require a vascular network for the successful
engraftment and survival of the bone substitute. However, host-derived
vascularization of implanted constructs is largely limited by the capacity of
host cells to invade and form in situ capillaries. 66 Creating functional and
perfusable microvascular systems, replicating the structure, biological
properties, heterotypic cell interactions and biomechanics of native micro-
vascular environment, represents nowadays an important bottleneck of bone
tissue engineering strategies. Below we describe important progress in
strategies to create vascularized tissues using biological cues.
Biological techniques for microvessel formation rely on heterotypic cell-
cell interactions and the cross-communication of cells with encapsulated
growth factors in the extracellular microenvironment. 63 Endothelial cells co-
cultured with human mesenchymal cells (hMSCSs) or perivascular cells have
resulted in the formation of microvascular networks. 63,66-71 This tendency
becomes more pronounced when endothelial and progenitor cells are
encapsulated in ECM-like hydrogels. These types of hydrogels can be che-
mically modified to allow homing mechanisms to cells and facilitate the
cross-talk of cell and the encapsulating matrix. Recently, Chen developed
vascularized methacrylated gelatin hydrogels by encapsulating blood-derived
endothelial colony forming cells (ECFCs) and bone marrow-derived MSCs
in a hydrogel matrix. 71 The results demonstrated an extensive formation of
capillary-like networks with lumens within the hydrogel structure. Pre-
vascularized hydrogels have the potential to be combined with osteo-
conductive materials to trigger angiogenesis in bone substitutes.

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