Page 376 - Advances in Biomechanics and Tissue Regeneration

18.4 ARTICULAR CARTILAGE AND TISSUE ENGINEERING 373

Of protein-based materials, fibrin and gelatin also create environments favorable for maintenance of the chondro-
cytic phenotype and chondrogenic differentiation of MSCs [101]. However, their mechanical properties are even
poorer than those of collagen; the materials are thus often used in combination with other materials to fabricate scaf-
folds with appropriate mechanical properties [95, 102]. Both fibrin and gelatin can contribute to scaffold structure or
encapsulation of growth factors to be later released to improve adhesion, proliferation, and chondrogenic differenti-
ation of cells contained within the scaffolds [103].

18.4.2.1.2 POLYSACCHARIDE-BASED SCAFFOLDS
Alginate and agarose were the first materials used for cartilage tissue engineering. Both polysaccharides are derived
from marine algae and exhibit useful gelation and cell encapsulation properties. Several studies found that these mate-
rials allowed chondrocytes and MSCs of various origins to express the characteristic ECM components of hyaline car-
tilage at both the RNA and protein levels [104]. However, although alginate gels easily in the presence of divalent ions,
elution of such ions by the surrounding environment causes gel degradation and loss of the soft mechanical properties
[102]. Recent studies have combined alginate with other polymers (natural or synthetic) to improve the mechanical
properties of scaffolds [105, 106]. Also, agarose, despite being biocompatible and nonimmunogenic and exhibiting
mechanical properties closer to those of hyaline cartilage, is not biodegradable by humans [107].
HA is a component of both articular cartilage and synovial fluid and supports chondrocyte phenotype retention and
matrix deposition and MSC chondrogenesis [108, 109]. Compared with other hydrogels formed of polyethylene glycol
or fibrin, cartilage formation was enhanced by HA hydrogels, emphasizing the important roles of biochemical cues
during cartilage formation. However, although scaffold biomaterials must be biodegradable, hyaluronidase action
must be controlled as this can compromise the strength of the newly formed matrix. Chemical modifications enhancing
or diminishing hyaluronidase activity may be required [95]. Also, HA is of low mechanical strength, as is also true of
other natural polymers mentioned earlier. HA is often combined with other polymers to improve mechanical prop-
erties [110, 111]; the properties of HA can also be enhanced by increasing the extent of cross-linking [102].
Chitosan (CHT) is a copolymer derived via alkaline deacetylation of chitin. CHT shares certain structural charac-
teristics with the GAGs of hyaline cartilage; CHT is thus an ideal scaffold for articular cartilage engineering. Another
advantage is that CHT is degraded by lysozyme to nontoxic products [112]. The life span of CHT is longer than that of
HA, favoring ECM deposition, and resorption can be modulated via chemical modification. CHT induces chondro-
genesis of both chondrocytes and MSCs [113].
Despite these advantages, limitations include poor cell adhesion [112], which is greatly improved on addition of
bioactive materials such as gelatin, collagen, or HA. We and others have observed that various growth factors favor
chondrogenesis within CHT-based scaffolds [113, 114].

18.4.2.2 Synthetic Materials
The use of materials of biological origin for cartilage tissue engineering is associated with risks of immunological
reactions, disease transmission, and limited availability. Synthetic materials lack these disadvantages, also allowing
control of mechanical properties (via chemical modifications), hydrophilia (a common problem, rendering cell nesting
difficult), and biodegradability [115, 116].
Poly(glycolic acid) (PGA), poly(L-lactic acid) (PLLA), and poly(L-ε-caprolactone) (PCL), as well as the copolymers
poly(lactic-co-glycolic acid) (PLGA) and poly(L-lactide-co-ε-caprolactone) (PLCL), have been widely used as synthetic
scaffolds for cartilage regeneration.
PCL exhibits elastic properties close to those of native cartilage [117]. PLGA is a degradable synthetic polymer
widely used in tissue engineering because of excellent biocompatibility, biodegradability, and mechanical strength
[118], in addition to low cytotoxicity and immunogenicity, compared with protein-based polymers [119]. PLCL is
degraded much more slowly than PLLA, avoiding the abrupt falls in pH reported in PLLA scaffolds [120]. To over-
come the shortcomings of synthetic materials, combinations with natural materials are commonly used to enhance
wettability and bioactivity. For example, PCL better supports chondrocyte growth when combined with CHT to
enhance the hydrophilia of PCL [121].
Therefore, scaffolds combining both natural and synthetic materials are of great interest, because they feature the
desirable properties of both materials.

18.4.3 Growth Factors

Although an appropriate scaffold and cell source are essential for tissue engineering, the use of growth and differ-
entiation factors inducing differentiation and maintenance of the chondrocytic phenotype are also essential. We will

II. MECHANOBIOLOGY AND TISSUE REGENERATION