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focus on imparting biomimetic functionality to orthopedic grafts and enabling their translation to the clinic.

But clinical translation remains elusive as researchers seek to understand how to achieve biological fixation or functional integration of tissue-engineered orthopedic grafts—of bone, ligaments, or cartilage—with each other and/or with the host environment. The challenge is rooted in the complexity of the musculo-skeletal system and the structural intricacy of both hard and soft tissues. These tissues, each with a distinct cellular population, must operate in unison to facilitate physiologic function and maintain tissue homeostasis. It is thus not surprising that the transition between various tissue types is characterized by a high level of heterogeneous structural organization that is crucial for joint function.

As shown in Figure 1, ligaments and tendons with direct insertions into bone exhibit a multitissue transition consisting of three distinct but continuous

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FIGURE 1 Common orthopedic tissue-to-tissue interfaces. Significant structural and compositional homology exists in the orthopedic tissue-to-tissue interfaces of the tendon-bone (Benjamin and Ralphs 1998), muscle-tendon (Larkin et al. 2006), cartilage-bone (Hunziker et al. 2002), and ligament-bone junctions (Iwahashi et al. 2010). Regeneration of these complex junctions is essential for integrative soft tissue repair and treatment of massive, multitissue injuries. Tendon-to-bone interface: AC = articular cartilage, B = bone, CF = calcified fibrocartilage, CT = connective tissue, TM = tidemark, UF = uncalcified fibrocartilage. Cartilage-to-bone interface: BM = bone marrow space, CC = calcified cartilage, R = radial zone, S = superficial zone, T = transitional zone.



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