Repair of Osteochondral Lesions - Engineered Bone: Tissue Engineering Intelligence Unit - page 177

We believe that this goal could be reached only by coordinated efforts in different areas, in
order to identify (i) an appropriate source of chondrogenic cells; (ii) the bioactive factors re-
quired by these cells; (iii) the specific features of 3D scaffolds in which cells can be grown; and
(iv) the regime of physical stimulation that a bioreactor should apply to enhance cartilage
development and maturation in a controlled environment. Advances in the generation of func-
tional cartilage grafts thus prompt for tight interactions between scientists with different back-
grounds, including medical doctors, cellular and molecular biologists, engineers, and physi-
cists.
Enhancement of the Integrative Capacity of Engineered Cartilage
Engineered cartilage constructs implanted in osteochondral defects have been reported to
remodel and fuse with the host subchondral bone, 84,115,116 possibly indicating that cartilage-bone
integration is not a major challenge. By contrast, the cartilaginous portion of these grafts often
does not integrate with the host cartilage to form a continuous, mechanically stable attach-
ment. Such lack of repair could lead to abnormal stress distribution during physiological activ-
ity and degeneration in the long term. 117 Elucidation of the relationships between adhesive
biomechanical properties and underlying cellular and molecular processes is necessary to de-
sign new integrative cartilage repair procedures. 118
In vitro model systems have been recently developed to study factors affecting
cartilage-cartilage integration without systemic effects and variability that are inherent to in
vivo studies. Bioreactor cultivation of engineered cartilage discs press-fit into native cartilage
rings indicated that an important factor for integrative cartilage repair is the presence of bio-
synthetically active cells capable of proliferating, filling the gaps at the tissue interface, and
progressively forming cartilaginous tissue. 119 In addition, proteoglycan removal from native
cartilage tissue by proteolytic enzymes was shown to increase the integrative properties of engi-
neered cartilage grafts but only if cells were present at the periphery of the construct. Therefore,
a partially developed-engineered cartilage, where cells are not yet totally “embedded” within a
dense extracellular matrix, could display larger integrative capacity. Using a partial apposition
configuration model, it was further demonstrated that integrative repair at the cartilage-cartilage
interface is mediated by deposition of newly synthesised collagen. 117 Based on all these find-
ings, one could envision strategies for enhanced integrative cartilage repair, whereby additional
chondrogenic cells or factors increasing collagen production are delivered at the time of graft
implantation, possibly after treatment of the chondral surface with proteolytic enzymes.
Identification of Appropriate Animal Models
The intrinsic repair capacity of articular cartilage significantly varies according to the spe-
cies, especially when comparing animals and humans. Therefore, animal models should not be
selected to demonstrate the success or failure of a certain cartilage repair procedure, but rather
to test selective variables of cartilage repair procedures and to understand general paradigms of
repair. The intrinsic chondrogenic capacity of human cells and their interactions with poly-
meric scaffolds have been studied subcutaneously in nude mice, although the absence of the
joint biochemical and biomechanical milieu could markedly bias the results. The feasibility of
new concepts in cartilage repair has been explored in rabbits, although no statement on the
efficacy of the treatments in humans may be derived. Questions related to graft survival and
patterns of remodelling under loading should be addressed in larger size animal models (e.g.,
sheep, goat, dog, and horse), although large differences in spontaneous healing and biological
behaviour of chondrocytes have been documented. A number of general requirements have
been described to make an animal model more suitable. 120 In particular, (i) the size of the
defect must be critical so that spontaneous healing does not occur without treatment; (ii) the
animals must be in the adult age in order to reduce the extent of spontaneous healing; (iii) the
evaluation must be performed also at a late time point (i.e., at least 1 year) in order to assess
possible long-term degenerative changes.