Biomaterials design for enthesis tissue engineering: A focus on diverse material types and their functional architectures

Entheses are specialized tissues that connect bones to soft tissues such as tendons and ligaments, playing a critical role in force transmission and joint movement. However, they are highly prone to injury and current surgical techniques often fail to fully restore their complex zonal architecture, resulting in high re-tear rates and suboptimal healing. Tissue engineering has emerged as a promising strategy to address these challenges by creating biomimetic constructs that replicate the native enthesis. A clear understanding of the distinct zones of the enthesis, each characterized by specific cellular and extracellular matrix (ECM) compositions, is essential for developing effective regeneration strategies. Recent design efforts have focused on two main approaches: (i) tissue-derived constructs that preserve the natural ECM, and (ii) synthetic material-based constructs that mimic the multiphasic or gradient properties of the native interface. Despite significant progress in replicating the enthesis's zonal structure and biochemical gradients, challenges remain in achieving mechanical properties comparable to native tissue. This review summarizes advances in biomimetic enthesis design, discusses their biological and biomechanical performance in vivo , and outlines future directions for translating these engineered constructs into clinically effective solutions. • Correlate biomimetic scaffold design with enthesis biomechanics. • Review tissue-derived, multiphasic, and gradient enthesis constructs. • Summarize structure and function trends from 2006 to 2025 in vivo studies. • Link multiscale design cues to mechanical and biological performance. • Identify translational challenges toward clinical enthesis regeneration.