ORTHOPEDIC INTERFACE TISSUE ENGINEERING: BUILDING THE BRIDGE TO INTEGRATED MUSCULOSKELETAL TISSUE SYSTEMS - Advanced Biomaterials: Fundamentals, Processing, and Applications - page 589

together at week one instead of four, suggesting the importance of cellular
interactions immediately post-seeding. Similarly, Gao et al. (Gao, Dennis,
Solchaga, Awadallah, Goldberg, and Caplan 2001) seeded mesenchymal stem
cell (MSC)-differentiated chondrogenic cells in a hyaluronan sponge and MSC-
differentiated osteogenic cells in a porous calcium phosphate scaffold. These scaf-
folds were then joined by fi brin sealant and implanted subcutaneously in syngeneic
rats, with continuous collagen fi bers observed between the two scaffolds six weeks
following implantation. Shortly after, Sherwood et al. designed a continuous
biphasic scaffold using the TheriForm™ 3D printing process and evaluated chon-
drocyte response on this scaffold (Sherwood et al. 2002). Using a sequential
polymerization technique, Alhadlaq and Mao fabricated bi-layered human
mandibular condyle-shaped osteochondral constructs with MSC-derived chon-
drocytes and osteoblasts encapsulated in distinct layers of polyethylene glycol-
diacrylate hydrogel (Alhadlaq and Mao 2005). Distinct cartilaginous and osseous
regions were observed post-implantation in a subcutaneous model, with integra-
tion between the two layers. These studies demonstrate the importance of multi-
phased scaffold design for multi-tissue formation.
Due to the complexity inherent at the soft tissue-to-bone interface and the
need to replace more than one type of tissue, stratifi ed scaffold design is critical
for interface tissue engineering. The aforementioned biphasic construct studies
represent a signifi cant advancement over strategies which have focused on regen-
erating only a single type of tissue on a construct with homogenous properties. In
addition, advanced scaffold design must take into consideration the regeneration
of the interface region between distinct tissue types. A biomimetic substrate is
essential for maintaining the mechanical strength and structural support, as well
as for providing the optimal growth environment for fi brocartilage formation (Lu
and Jiang 2006).
The multi-tissue transition from ligament to fi brocartilage and to bone at the
insertion site poses signifi cant challenges for interface tissue engineering as more
than three distinct types of tissue are present. In addition to supporting the growth
and differentiation of relevant cell types, the ideal scaffold for interface tissue
engineering must direct heterotypic and homotypic cellular interactions while
promoting the formation and maintenance of controlled matrix heterogeneity.
Consequently, the scaffold should exhibit a gradient of structural and material
properties mimicking those of the native insertion zone.
Compared to a homogenous structure, a scaffold with pre-designed inhomo-
geneity may better sustain and transmit the distribution of complex loads inher-
ent at the ACL - to - bone interface. The interface scaffold must also be biodegradable
and exhibit mechanical properties comparable to those of the ligament insertion
site. Finally, the tissue engineered graft must be easily adaptable with current
ACL reconstruction grafts, or pre-incorporated into the design of ligament
replacement grafts, in order to enable in vivo graft integration. Modeled after the
native ACL-to-bone interface and inspired by the structure-function relationship
inherent at the ACL-to-bone interface, Spalazzi et al. were the fi rst to report on
the design of a multi-phased scaffold for interface tissue engineering (Spalazzi