Scaffold-based tissue engineering strategies for soft-hard interface regeneration

Repairing injured tendon or ligament attachments to bones (enthesis) remains costly and challenging. Despite superb surgical management, the disorganized enthesis newly formed after surgery accounts for high recurrence rates after operations. Tissue engineering offers efficient alternatives to promote healing and regeneration of the specialized enthesis tissue. Load-transmitting functions thus can be restored with appropriate biomaterials and engineering strategies. Interestingly, recent studies have focused more on microstructure especially the arrangement of fibers since Rossetti successfully demonstrated the variability of fiber underspecific external force. In this review, we provide an important update on the current strategies for scaffold-based tissue engineering of enthesis when natural structure and properties are equally emphasized. We firstly described compositions, structures and features of natural enthesis with their special mechanical properties highlighted. Stimuli for growth, development and healing of enthesis widely used in popular strategies are systematically summarized. We discuss the fabrication of engineering scaffolds from the aspects of biomaterials, techniques and design strategies and comprehensively evaluate the advantages and disadvantages of each strategy. At last, this review pinpoints the remaining challenges and research directions to make breakthroughs in further studies.