Hierarchical and heterogeneous hydrogel system as a promising strategy for diversified interfacial tissue regeneration.

Despite breakthroughs in tissue engineering, a tremendous problem still lies in repairing the interfacial tissue which connects soft tissue to hard tissue, particularly cartilage-bone, tendon/ligament-bone, and cementum-ligament-bone interfaces. The challenge comes from the complicated biophysical and biochemical characteristics of interfacial tissues, involving a graded variation of chemical components, structures, and mechanical properties as well as a heterogeneous cell distribution from the soft end to the hard end. Accordingly, significant progress has been made in the design of hierarchical and heterogeneous hydrogel systems in order to solve this problem. Advanced programmable technologies, such as 3D printing and microfluidic platforms, have shown potential in constructing templates or scaffolds with tissue-specific characteristics. The structural specialty of the three aforementioned interfacial tissues is summarized in this review. Then the text concentrates on how to utilize different scale hydrogels (from chemical variation, nanoscale, microscale to cellular regulation) to fabricate gradient constructions for regenerating interfacial tissues, together with in vitro and in vivo outcomes. In particular, the fabrication of continuous gradients is highlighted in this review. Promisingly, the versatile designs involved in fabricating hierarchical and heterogeneous hydrogel systems are predicted to tackle the unsolved problems, and this interfacial tissue engineering methodology is expected to expand its use in therapeutic applications.