MICRO-AND NANOENGINEERING APPROACHES TO DEVELOPING GRADIENT BIOMATERIALS SUITABLE FOR INTERFACE TISSUE ENGINEERING - Micro and Nanotechnologies in Engineering Stem Cells and Tissues - page 56

change in the structural organization and nature of the tissue. Interfacial tissues
are complex structures with heterotypic cells surrounded by subtle variations in
the ECM, which contains physical, chemical, and mechanical cues. Therefore,
scaffolds with graded physical properties are better suited to promoting interface
reconstruction.
In tissue engineering, the most frequently used physical gradients are porosity
gradients, stiffness gradients, and surface gradients. Porous scaffolds fabricated from
biomaterials have also been widely used in tissue reconstruction. In fact, scaffolds
with appropriate porosities and interconnected pores with different size ranges are
typically required to facilitate cell infiltration and other essential cellular functions.
A good example of a physical porosity gradient in the native body is the interface
between the cortical and trabecular bone regions, which exhibits a smooth and
continuous transition from low porosity at the cortical bone region to high porosity at
the trabecular bone region. 11 Porosity and pore size are very important features of a
tissue scaffold that greatly affect cell behaviors, particularly cell adhesion, migra-
tion, proliferation, and phenotype expression. 12 For example, whereas endothelial
cells showed the highest proliferation and ECM production profiles when cultured on
scaffolds with a 5

m pore size compared with scaffolds with larger pore sizes,
hepatocytes preferred 20

m

m
pore sizes. 13,14 Consequently, when cells are cultured on a scaffold that has a gradient
of porosity or pore size, they tend to preferentially colonize in some areas rather than
others. For example, cells from a mixture of chondrocytes, osteoblasts, and fibro-
blasts cultured on a pore-size gradient colonized in different areas depending on the
size of the pores. 15 Chondrocytes and osteoblasts grew well on the larger pore size
area, whereas fibroblasts preferred the smaller pore size area. Woodfield et al.
showed that a pore size gradient from 200 to 1650

m m, fibroblasts 90-360 m m, and osteoblasts 100-350 m

m promoted an anisotropic
bovine chondrocyte cell distribution and anisotropic glycosaminoglycan (GAG)
deposition. 16 This anisotropic cell distribution caused by a gradient in porosity or
pore size can be used to investigate the interactions of the cells with the scaffold,
control cell migration and proliferation, guide tissue ingrowth, or mimic a physio-
logical interface.
Biomaterials with gradients in mechanical properties are often used to engineer
interfacial tissues. A good example of a biomechanical gradient in the body is the
tendon-to-bone interface, where the stiffness of the bone gradually converts to the
elasticity of the ligament. 17,18 In tissue engineering, it is important that a scaffold
matches the mechanical properties of the host tissue. For example, in bone
regeneration, if the scaffold has lower mechanical properties than the bone itself,
the scaffold will not be able to withstand the physiological load and may break. In
contrast, if the scaffold has higher mechanical properties than the bone, it will shield
the bone from the load and thus may cause bone resorption (stress-shielding effect).
A great deal of research is underway to mimic the mechanical properties of bone
using gradient biomaterials.
Material stiffness is another key property that affects cell behaviors, notably cell
spreading, proliferation, and differentiation. This importance of stiffness exists
because cells can precisely sense physical stress and adjust the rigidity of their

m