Biomedical Engineering Reference
In-Depth Information
14.3.4 Graded Structure in Hydrogels and Stiff Polymers
Gradient scaffolds made from both hydrogels and stiffer materials have been explored
in an effort to match the soft tissue-bone interfaces. Hydrogels may mimic the ECM
in terms of their high water content, viscoelasticity, and/or diffusive transport
characteristics [ 47 , 48 ]. They can further be tailored to mimic a 3D microenviron-
ment within a tissue. Due to advances in material chemistry, a wide range of
hydrogels have been synthesized with tunable physical, chemical, and functional
properties. Commonly employed polymers for 3D hydrogel fabrication include
blends or copolymers of alginate, agarose, gelatin, hyaluronic acid, chitosan, poly
(ethylene glycol) (PEG), and collagen. Various methods have been developed to
create chemical and physical gradients on hydrogel scaffolds. Holland et al . [ 42 ]
used a multi-step cross-linking procedure to fabricate multilayered oligo(poly(eth-
ylene glycol) fumarate) (OPF) osteochondral scaffolds with good integration
between layers. Hydrogels with concentration gradients in the cell-adhesion ligand
Arg-Gly-Asp-Ser (RGDS) [ 49 ], gradients in elastic modulus or pore size [ 50 , 51 ],
and fibril density have been widely explored. Physical gradients that were several
hundreds of microns in length were fabricated by making different concentrations of
pre-polymer solutions that were allowed to diffuse into each other and further
stabilized by appropriate cross-linking methods. Multiple growth factors and
proteins have been immobilized in different directions in hydrogels and their
concentration-dependent response in rate and orientation of cell migration has
been studied. Chemical gradients of encapsulated signals were also made by
microfluidic channels embedded in hydrogels [ 52 ], or by pumping different polymer
solutions at controllable flow rates [ 53 ] that were further stabilized by photo or
thermal cross-linking methods [ 54 , 55 ]. Stepwise stiffness gradients and patterned
interlocking blocks of different stiffnesses have been produced in hydrogels [ 56 ].
These techniques have been used to create gradients of soluble factors, proteins,
beads, and even cells within hydrogel networks [ 44 , 57 , 58 ]. Du et al . [ 58 ]
demonstrated a technique to rapidly produce centimeter scale concentration
gradients of cells and microbeads by flow convection and high fluidic shear in a
microfluidic channel. They were able to generate cross-gradients in particles and
hydrogels by using alternating flows, superposing gradients of two species resulting
in anisotropic material gradients. Chatterjee et al. showed that scaffolds with
increasing gradients of compressive modulus can direct osteoblast differentiation
and mineralization [ 59 ]. Hydrogels with mineral gradients were generated when
osteoblasts were encapsulated in PEG hydrogels with an increasing gradient of
modulus from 10 to 300 KPa (Fig. 14.2 ). This is a promising approach for engineer-
ing seamless tissue interfaces for hard and soft tissues without the use of expensive
growth factors [ 59 ].
Chemical and physical gradient structures to mimic tissue interfaces can be
developed by combining these gradient protocols with appropriate cross-linking
methods. A recent review on “Biomimetic gradient hydrogels for tissue engineer-
ing” [ 60 , 61 ] elaborately discussed all of these aspects that have been investigated
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