Future Directions - Articular Cartilage Tissue Engineering - page 93

to hyperacute rejection due to the avascularity of the tissue; thus, cartilage is considered to be rel-
atively non-immunogenic [ 823 , 824 ] . However, the cartilage matrix, particularly the α -galactosyl
carbohydrate structure, or epitope, is a source of immunogenicity that leads to tissue destruction
with xenograft implantation, but only in humans and primates [ 825 - 828 ]. For instance, implanted
porcine and bovine articular cartilage in cynomolgus monkeys elicited extensive humoral response to
the xenografts, leading to chronic graft rejection with fibrous encapsulation and peripheral leukocyte
infiltration [ 829 ]. In a follow-up study, implanted porcine or bovine articular cartilage in cynomol-
gus monkeys resulted in the increase of anti- α -galactosyl IgG by up to 100-fold, accompanied by
increased complement-mediated cytotoxicity; thus indicating a chronic rejection response to the
tissue [ 830 ]. Finally, porcine articular cartilage pre-treated with α -galactosidase to remove the α -
galactosyl epitope resulted in a significant reduction in the inflammatory response to the xenograft
and decreased T lymphocyte infiltration into the tissue in the cynomolgus monkey [ 831 ].
As only humans and primates do not express the α -galactosyl epitope and, therefore, produce
anti- α -galactosyl antibodies, an α -1,3-galactosyltransferase knockout mouse has been developed as a
small animal model to study the immune response to this epitope [ 832 ]. These mice mimic humans
and primates in that they do not produce the α -galactosyl epitope as the α -galactosyl epitope is
formed by α -1,3-galactosyltransferase. This model has been used to assess in vivo immunogenicity
and response to α -galactosyl production of a decellularized vascular graft [ 833 ] and may be employed
to examine xenogeneic cartilage in the future.

5.5 BUSINESS ASPECTS ANDREGULATORY AFFAIRS

INCARTILAGETISSUE ENGINEERING

A bulk of this text has thus far been concerned with how tissue engineered constructs can be produced.
Growth factors and bioreactors, used in combination with a variety of cells and scaffolds, are intended
to result in functional cartilage implants. Current therapies, including autologous, allogeneic, and
xenogeneic transplants have been presented, as well as other emerging technologies that do not
employ cells or tissues at all. Depending on the indication, successful articular resurfacing may
eventually be achieved using a variety of products and methods. These products might also include
glues and fixatives specifically developed to adhere a piece of engineered cartilage to the native tissue,
as well as tools and enzymes that prepare the osteochondral or chondral defect to receive an implant.
The above are but a short, categorical list of the treatment possibilities that can come to market. Most
of the cartilage tissue engineering technologies described in this text are still in their experimental
stages, and their safety and efficacy are yet to be verified. The pathway potential products can take
in demonstrating safety and efficacy will depend on the nature of the product and its intended use.
This is an important consideration from a business perspective because some routes take longer
and cost more than others. A brief introduction to the regulatory bodies of the US Food and Drug
Administration (FDA) will be presented, and pathways to regulatory approval will be provided in
this section.