Repair of Osteochondral Lesions - Engineered Bone: Tissue Engineering Intelligence Unit - page 170

Fibrin , currently utilised in clinic as fibrin glue, is a natural polymer that forms during
blood coagulation and plays an important role in hemostasis and wound healing.
Heparin-containing fibrin hydrogels have been reported to slowly and regularly deliver growth
factors presenting heparin binding affinity, including FGF-2. 46
Alginates are negatively charged unsulfated copolymers of L-glucuronic and D- mannuronic
acids extracted from brown algae. They cross-link in the presence of multivalent cations (mostly
Ca ++ ) to form an open-lattice hydrogel. The large average pore size of the mesh allows easy
diffusion of macromolecules. The relatively mild gelation process of cross-linking has enabled
not only biological proteins but also cells and DNA to be incorporated into alginate matrices
without significant loss of full biological activity. 47
Hyaluronic acid has unique physicochemical properties and distinctive biological func-
tions. It binds specifically to proteins in the extracellular matrix and on the cell surface, thereby
playing a role in cartilage matrix stabilisation 48 and cell mobility. 49 Partially esterified hyalu-
ronic acid has been recognised as particularly suitable for controlled peptide release or protein
delivery. 50 For instance, when loaded with BMP-2 in synergy with IGF-I, cross-linked high
molecular weight hyaluronic acid was reported to promote excellent cell infiltration and carti-
lage formation. 51
Use of Matrices Made of Synthetic Polymers
The use of synthetic polymers introduces high flexibility in the modulation of matrix physi-
cochemical properties, and thus of their delivery kinetics for specific bioactive factors. Novel
polymer processing techniques also allow enhanced maintenance of the biological functional-
ity of the incorporated factors. 52,53
Most synthetic matrices currently used for delivery of bioactive factors are made of polylactic
acid or polyglycolic acid homo- or heteropolymers. An example of such a synthetic matrix used
for delivery of factors in cartilage repair is a 50:50 poly-DL-lactide-coglycolide scaffold loaded
with TGF β 1 and implanted in 7-mm osteochondral defects in goats. The study showed the
potential for TGF β 1 delivered by biodegradable scaffolds to improve the quality of cartilage
repair. 54
Since most proteins have free aminoacid groups in their sequences, they can be covalently
linked to a polyethylene glycol (PEG) hydrogel network. This covalent attachment provides a
means to achieve long-term controlled release of bioactive molecules. Upon hydrolysis, PEG
hydrogels degrade into low molecular weight PEG derivatives, which can be easily cleared by
the body. 55,56 Alternatively, the PEG network can be used to encapsulate microspheres con-
taining bioactive factors. Indeed, microspheres containing IGF-I and TGF β 1 photoencapsulated
with bovine chondrocytes in PEG-based hydrogels promoted increased production of glycosami-
noglycans (GAG). 57
Advances in polymer science have recently led to the development of vehicles capable of
delivering multiple factors with distinct kinetics. 58 The method, although currently limited to
the delivery of only two factors and not specifically designed for the repair of cartilage lesions,
addresses the important issue of releasing different factors at different temporal stages, which is
a key for a successful enhancement of tissue regeneration.
Delivery of Factors by Gene Transfer
Bioactive molecules usually have a relatively short half-life. When they are administered
directly in the joint, the maintenance of effective concentrations necessitates either very high
initial doses or repeated treatment. The approach of gene transfer may circumvent these limi-
tations, providing an enhanced and long-lasting production of bio-effectors. Thus, the intro-
duction of appropriate genes directly at the site of injury could possibly initiate the healing
response, accelerate the healing process and improve the quality of the repair tissue.
The feasibility of gene transfer in cartilage repair has been so far investigated mostly in the
context of rheumatoid arthritis and osteoarthritis. In a number of animal models of inflamma-
tory arthritis, the delivery of anti-inflammatory agents has shown efficacy in ameliorating vari-
ous joint pathological symptoms. 59-61