Biomedical Engineering Reference
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material that reduced the stress concentrations at the interface. Pre-osteoblasts
preferentially adhered and proliferated in regions with higher calcium phosphate
content along the gradated scaffold. Liu et al. [ 63 ] prepared a gradient collagen/
nano-HA composite scaffold, by a biomimetic diffusion-precipitate method.
Nano-HA was crystallized in the interior of a collagen scaffold to form a composi-
tional and structural gradient. Kon et al . [ 64 ] looked into fabrication of multilayered
gradient artificial ECMs composed of type I collagen and HA. The cartilaginous
layer, consisting of Type I collagen, had a smooth surface. The mineral phase,
represented by magnesium-hydroxyapatite, was directly nucleated onto collagen
fibers during their self-assembling. The intermediate (tidemark-like) layer consisted
of a combination of collagen and HA. The compositions of type I collagen and HA
varied in each region (cartilage region: 100% type I collagen; transition region: 40%
HA and 60% type I collagen; and bone region: 70% HA and 30% type I collagen).
The intermediate and the lower layers were obtained by nucleating nanostructured
nonstoichiometric hydroxyapatite into self-assembling collagen fibers, similar to the
natural biological neo-ossification process. Chondrocytes were seeded only in the
cartilage region and the scaffolds were transplanted into the osteochondral defect.
The regeneration of bone and cartilage was found to significantly enhance with these
graded artificial ECMs compared to that of the control group in sheep model as well
as in early clinical trials in human beings [ 65 ].
Hydrogel scaffolds are good candidates for engineering the soft tissues at the
interface. They can be chemically modified to couple peptides to enhance cell
adhesion, and are good delivery vehicles for bioactive signals and cells. Gradients
in these encapsulated components can be obtained by simple diffusion, flow
convection or by creating microfluidic channels within the hydrogels. Hydrogels
with gradients in material composition, porosity, and mechanical properties can be
fabricated by interdiffusion of two different polymers and by effective cross-
linking. A gradient in osteoconductive hydroxyapatite is a promising approach to
enhance mineralization as well as stiffness to match the mechanical properties of
the soft-hard tissue interface. Osteoconductive inorganic materials can be effi-
ciently nucleated within the hydrogels and integration at the interface can be
achieved by diffusion of hydrogels into the bony phase along with appropriate
cross-linking methods.
14.3.5 Gradients in Pore Architecture
The scaffold design should incorporate anisotropic pore architecture to accommo-
date the different types of cells and ECM distribution at the interface. Studies have
suggested that the pore size and substrate surface influence the cell morphology and
phenotypic expression, while porosity influences the cell proliferation. Research has
revealed that 70-120
m pores were suitable for chondrocyte ingrowth [ 66 ],
m
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