A major focus in the field of orthopaedic tissue engineering is the development of tissue engineered bone and soft tissue grafts with biomimetic functionality to allow for their translation to the clinical setting. One of the most significant challenges of this endeavor is promoting the biological fixation of these grafts with each other as well as the implant site. Such fixation requires strategic biomimicry to be incorporated into the scaffold design in order to re-establish the critical structure-function relationship of the native soft tissue-to-bone interface. The integration of distinct tissue types (e.g. bone and soft tissues such as cartilage, ligaments, or tendons), requires a multi-phased or stratified scaffold with distinct yet continuous tissue regions accompanied by a gradient of mechanical properties that mimics that of the multi-tissue transition between bone and soft tissues. This review discusses tissue engineering strategies for regenerating common tissue-to-tissue interfaces (ligament-to-bone, tendon-to-bone or cartilage-to-bone), and the strategic biomimicry implemented in stratified scaffold design for multi-tissue regeneration. Potential challenges and future directions in this emerging field will also be presented. It is anticipated that interface tissue engineering will enable integrative soft tissue repair, and will be instrumental for the development of complex musculoskeletal tissue systems with biomimetic complexity and functionality.

Soft tissue-to-bone transitions, such as the osteochondral interface, are complex junctions that connect multiple tissue types and are critical for musculoskeletal function. The osteochondral interface enables pressurization of articular cartilage, facilitates load transfer between cartilage and bone, and serves as a barrier between these two distinct tissues. Presently, there is a lack of quantitative understanding of the matrix and mineral distribution across this multitissue transition. Moreover, age-related changes at the interface with the onset of skeletal maturity are also not well understood. Therefore, the objective of this study is to characterize the cartilage-to-bone transition as a function of age, using Fourier transform infrared spectroscopic imaging (FTIR-I) analysis to map region-dependent changes in collagen, proteoglycan, and mineral distribution, as well as collagen organization. Both tissue-dependent and age-related changes were observed, underscoring the role of postnatal physiological loading in matrix remodeling. It was observed that the relative collagen content increased continuously from cartilage to bone, whereas proteoglycan peaked within the deep zone of cartilage. With age, collagen content across the interface increased, accompanied by a higher degree of collagen alignment in both the surface and deep zone cartilage. Interestingly, regardless of age, mineral content increased exponentially across the calcified cartilage interface. These observations reveal new insights into both region- and age-dependent changes across the cartilage-to-bone junction and will serve as critical benchmark parameters for current efforts in integrative cartilage repair.

The primary current challenge in regenerative engineering resides in the simultaneous formation of more than one type of tissue, as well as their functional assembly into complex tissues or organ systems. Tissue-tissue synchrony is especially important in the musculoskeletal system, whereby overall organ function is enabled by the seamless integration of bone with soft tissues such as ligament, tendon, or cartilage, as well as the integration of muscle with tendon. Therefore, in lieu of a traditional single-tissue system (e.g. bone, ligament), composite tissue scaffold designs for the regeneration of functional connective tissue units (e.g. bone-ligament-bone) are being actively investigated. Closely related is the effort to re-establish tissue-tissue interfaces, which is essential for joining these tissue building blocks and facilitating host integration. Much of the research at the forefront of the field has centered on bioinspired stratified or gradient scaffold designs which aim to recapitulate the structural and compositional inhomogeneity inherent across distinct tissue regions. As such, given the complexity of these musculoskeletal tissue units, the key question is how to identify the most relevant parameters for recapitulating the native structure-function relationships in the scaffold design. Therefore, the focus of this review, in addition to presenting the state-of-the-art in complex scaffold design, is to explore how strategic biomimicry can be applied in engineering tissue connectivity. The objective of strategic biomimicry is to avoid over-engineering by establishing what needs to be learned from nature and defining the essential matrix characteristics that must be reproduced in scaffold design. Application of this engineering strategy for the regeneration of the most common musculoskeletal tissue units (e.g. bone-ligament-bone, muscle-tendon-bone, cartilage-bone) will be discussed in this review. It is anticipated that these exciting efforts will enable integrative and functional repair of soft tissue injuries, and moreover, lay the foundation for the development of composite tissue systems and ultimately, total limb or joint regeneration.