Mechanical Discontinuity and Mechanobiology at the Graft-Host Junction: Enhancing Functional Integration in...

Tissue-engineered constructs (TECs) offer promising alternatives to autologous grafts and conventional artificial implants for the repair or replacement of damaged soft tissues. Nevertheless, their clinical translation remains limited for several reasons. While biomaterial biocompatibility, immune regulation, and the utilization of stem cells have received considerable attention, the mechanical environment of the graft-host junction (GHJ), particularly the mechanical mismatch between grafts and host tissues, has not been paid enough attention. This review proposes that mechanical continuity is as fundamental as biological compatibility for durable graft integration and examines the GHJ as a spatiotemporally evolving mechanobiological system coupled with immune surveillance and responses. In this review, we first draw lessons from two natural tissue transitions that involve changes in mechanical properties: the development of the muscle-tendon-bone unit and skin-wound healing processes. We then survey current clinical applications of soft-tissue TECs. It comes out that complications frequently arise at or near the graft-host junction; however, the limited clinical characterization of GHJ mechanics also indicates that interface mechanobiology remains substantially overlooked in TEC clinical applications. In view of this situation, we analyze the potentially critical roles of mechanobiology at the GHJ, characterizing graft integration as intertwined spatiotemporal processes governed by both general and mechano-immune coupling. We finally advocate for incorporating mechanobiological considerations into graft interface design to achieve functional integration in clinical TEC applications and highlight AI-assisted inverse design and multimaterial 3D bioprinting as the most promising technologies to realize mechanobiological design and fabrication of the TEC junction portion.