ORTHOPEDIC INTERFACE TISSUE ENGINEERING: BUILDING THE BRIDGE TO INTEGRATED MUSCULOSKELETAL TISSUE SYSTEMS - Advanced Biomaterials: Fundamentals, Processing, and Applications - page 582

design parameters. These understandings will collectively enable the design of
stratifi ed scaffolds optimized for supporting heterotypic cellular interactions as
well as the development of controlled matrix heterogeneity and multi-tissue
stratifi cation mimicking those found at the soft tissue-to-bone junction. Recent
advances in each of these three critical areas in interface tissue engineering will
be discussed in the following sections.
17.3 MECHANISM OF INTERFACE REGENERATION: ROLE OF
HETEROTYPIC CELLULAR INTERACTIONS
An understanding of the basic mechanisms governing interface regeneration is
required for any successful interface tissue engineering effort. One of the funda-
mental questions to be addressed is how distinct boundaries between different
types of connective tissues are re-established post injury. As described above and
shown in Figure 17.1, the native ACL-bone insertion consists of a linear progres-
sion of three distinct matrix regions: ligament, fi brocartilage, and bone, each
exhibiting a characteristic cellular phenotype and extracellular matrix composi-
tion. Currently, the mechanisms of interface regeneration and homeostasis of
these multi-tissue boundaries are not known. It is likely that communication
among the cell types residing within these three distinct tissue regions—namely
fi broblasts, fi brochondrocytes and osteoblasts—plays an important role in inter-
face homeostasis and regeneration post injury.
While tendon-to-bone healing following ACL reconstruction does not lead to
the re-establishment of the native insertion, it has been well documented that a
fi brovascular tissue is formed within the bone tunnel (Anderson et al. 2001; Batra
et al. 2002; Blickenstaff, Grana, and Egle 1997; Chen et al. 2003; Chen et al. 1997;
Eriksson, Kindblom, and Wredmark 2000; Grana et al. 1994; Liu et al. 1997; Panni
et al. 1997; Rodeo et al. 1993; Song et al. 2004; Thomopoulos et al. 2002; Yoshiya
et al. 2000). This layer later matures and reorganizes into fi brocartilage - like or
fi brovascular tissue during the healing process. While this neo-fi brocartilage tissue
is non-anatomical, these observations demonstrate that a fi brocartilage - like tissue
can be regenerated in vivo between soft tissue and bone. Specifi cally, fi brocarti-
lage formation is usually localized to areas where the tendon graft directly con-
tacts the bone. When damage to the interface region during injury results in the
non-physiologic exposure of normally segregated tissue types (that is, bone and
ligament), heterotypic cellular interactions (osteoblast-fi broblast) are likely criti-
cal for initiating and directing the repair response that results in the regeneration
of a fi brocartilage interface between these two types of tissue. Moreover, in vivo
cell-tracking studies have revealed that the tendon graft is populated by host cells
within one week of implantation (Kobayashi et al. 2005).
Since the source and nature of these host cells are not known, cell types
other than osteoblasts and fi broblasts may be involved in fi brocartilage forma-
tion. When Fujioka et al. sutured the Achilles tendon to its original attachment
site, both cellular organization resembling that of the native insertion and the