Repair of Osteochondral Lesions - Engineered Bone: Tissue Engineering Intelligence Unit - page 169

for a defined period of time may provide a critical initial input to expedite regeneration pro-
cesses. Success of the approach will depend on the choice both of the factor(s) to administer
and the way of release and delivery.
Selection of Factors
Coordinated in vivo and in vitro experiments may guide the selection of the effector(s) that
should induce cell proliferation and/or differentiation. Those retaining major attention are
listed here below.
Growth factors of the TGF- β superfamily are known to participate in endochondral bone
formation and fracture callus healing processes. BMPs are important signalling molecules in-
ducing limb bud development during embryogenesis, 24 ectopical bone formation 25 and differ-
entiation of mesenchymal progenitor cells into osteoblasts and chondrocytes. 26-29 TGF- β 1 has
emerged as one of the key factors promoting synthesis of type II collagen and aggrecan core
protein and down-regulating metalloproteinases. 30-32
FGF-2 is regarded to date as the most potent mitogen for chondrocytes. By contrast, this
factor may have opposite effects on matrix deposition and accumulation, since it promotes
both anabolic and catabolic activities. 33,34 Therefore, FGF-2 could be delivered only in early
phases of tissue repair.
Insulin and insulin-like growth factors (IGF-I and IGF-II) all modulate cartilage matrix
production. Insulin alone is much less potent than IGF-I in stimulating collagen synthesis but
strongly enhances proteoglycan deposition. IGF-I maintains chondrocyte metabolism in carti-
lage homeostasis, stimulates chondrocyte synthetic and mitotic activities and inhibits
chondrocyte-mediated matrix catabolism. Also IGF-II can stimulate proteoglycan synthesis
but, like insulin, is much less effective than IGF-I. 35,36
EGF alone has no effect on chondrocyte proliferation. Together with insulin, EGF syner-
gistically stimulates proteoglycan synthesis and induces chondrocyte proliferation. 37 PDGF
also enhances proteoglycan deposition but to a lower extent as compared to the other described
factors. 38
Direct or Matrix-Based Delivery of Factors
Attempts of local molecular treatment have been performed in rodent models using TGF- β 1
and FGF-2, administered either by sequential injections or constant release through osmotic
pumps. Both delivery systems resulted in successful regeneration of articular cartilage and sub-
chondral bone. 39,40 However, other authors reported adverse effects secondary to local admin-
istration, including inflammatory joint response, synovial hyperplasia, proteoglycan loss, carti-
lage destruction and osteophyte formation. 41,42
In the past few years, several matrix-based delivery systems have been developed and tested
for cartilage repair. The use of a matrix would help not only stabilising the factors and control-
ling their delivery, but also providing a structural template filling the osteochondral lesion. The
ideal matrix should meet essential requirements as being nonimmunogenic, nontoxic,
biocompatible, biodegradable and easily manufactured. Issues related to biocompatibility, bio-
logical response and immunotoxicity evaluation of release systems have been reviewed by Ander-
son and Langone. 43 Here we describe some examples of delivery systems based on matrices
made of naturally occurring or synthetic polymers.
Use of Matrices Made of Naturally Occurring Polymers
Collagen is a physiological substance, which can be prepared in solution or shaped in mem-
brane film, thread or sponge. Although derived from xenogeneic sources (mostly porcine skin),
purification techniques can now eliminate the immunogenic telopeptides that used to prompt
foreign body responses to implantation. In such, collagen sponges impregnated with osteo-
genic proteins from demineralized bone matrix 44 or BMP-2 45 were prone to induce ectopic
cartilage formation or improve healing of full-thickness articular defects.