Artificial Scaffolds and Mesenchymal Stem Cells for Hard Tissues - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 181

In general, an artificial substrate should provide an environment similar to the
ECM and the SC niche [ 94 , 199 , 200 ]. Three-dimensional culture systems, which
generally induce a more rounded, spheroidal cell morphology in comparison to
standard 2D culture systems, are by themselves already influencing SC fate [ 151 ],
and it is the beauty of the system that even our very limited understanding of the
SC microenvironment already leads to reasonable results due to the intrinsic set of
possible SC fates. Nevertheless that should not obviate further efforts towards a
better understanding of the SC and its fate within its natural or artificial micro-
environment, for a future use of the system in regenerative medicine.

5 Scaffold-Cell Interaction in Hard Tissue Engineering

5.1 MSCs on Scaffolds for Bone Defects

Bone defects must be divided into small bone defects and critical-size defects
(CSD) of the bone that will not heal during the lifetime of an animal, when used in
the preclinical field of orthopedic and trauma surgery. CSD need cells and scaffold
material to bridge the gap. These bone substitutes must be evaluated for their
biocompatibility and preferably they should also allow osteoinductivity and
osteoconductivity. To achieve this, the cell type (SCs or differentiated cells) and
the physicochemical and mechanical factors of the SC environment must be
considered.
An overview of the SCs used to generate the major cells of a bone tissue,
namely osteoblasts, osteoclasts, and chondrocytes, can be found in zur Nieden's
publication [ 201 ]. But the cell type alone does not give the full story. Osteoin-
ductivity and osteoconductivity must match the state of the respective cell with
which the scaffold is loaded, because a SC or a differentiating cell will react
differently to an inducing signal. Hsiong and colleagues showed that SCs were less
sensitive in their uncommitted state to a model cell adhesion ligand (arginine-
glycine-aspartic acid [RGD]-containing peptide) presented from hydrogels of
varying stiffness than cells differentiated into the osteoblast lineage [ 174 ].
Several mechanical factors and chemicals such as oxygen or calcium, with or
without additional enzymes, are known to be key players in influencing SC fate
towards osteogenesis. The regulation of osteogenesis and chondrogenesis during
skeletogenesis in regulating limb development and regenerative events such as
fracture repair are dependent on mechanical signals influencing MSCs [ 202 ].
The effect of matrix stiffness on osteo-differentiation already mentioned (see
Sect. 4.2.1 ) often shows an additive or even synergistic effect with soluble factors.
The effect of matrix stiffness on the differentiation of MSCs in response to TGF-b
can promote MSC differentiation into either smooth muscle cells (SMCs) or
chondrogenic cells [ 203 ]. The small GTPase RhoA and its effector protein

ROCKII regulate fluid-flow-induced osteogenic differentiation via isometric