Biomaterials with stiffness gradient for interface tissue engineering

Interface tissue engineering is a rapidly growing field that aims to develop engineered tissue alternates with the goal of promoting integration between multiple tissue types. Engineering interface tissues is a challenging process, which requires biomaterials with specific composition, stiffness, cell types, and biochemical molecules. Among these, stiffness-controllable substrates have been developed to investigate the effect of stiffness on cell behavior. Especially these substrates with graded stiffness are advantageous since they allow multiple cell types differentiation and the following tissue development. In this review, we highlight various types of manufacturing techniques that can be applied to fabricate scaffolds with stiffness gradient, discuss methods to characterize them, and gradient biomaterials for regulating cellular behavior including attachment, migration, proliferation, and differentiation. We also address fundamentals of interface tissue organization, and stiffness gradient biomaterials for interface tissue regeneration. Potential challenges and future prospects of this emerging field are also included.