Engineering the Enthesis: Mechanical Constraints, Functional Objectives, and Biomaterial Design Strategies

Abstract

Fibrocartilaginous entheses are heterogeneous connective tissues that link soft tissues to bone in key joints and are crucial for mobility where the available attachment area is minimal. Current replacements fail to sufficiently replicate the compositional and structural gradients of the native enthesis, which transitions from ligamentous tissue to fibrocartilage to mineralized tissue within millimeters. Tissue engineering and tissue characterization efforts have largely focused on replicating enthesis heterogeneity, often without explicitly considering how this heterogeneity supports specific mechanical and biological functions. In this Review, we first define the enthesis as a tissue that performs five key functions under the overarching role of dispersing stress at locations of pronounced stiffness change within joints. Using this functional perspective, we critically examine characterization studies across anatomically distinct fibrocartilaginous entheses, relating measured parameters to particular functions, emphasizing shared features across entheses, and highlighting location‑specific differences where relevant. This analysis identifies the current state‑of‑the‑art in enthesis characterization and exposes key gaps in how structure–function relationships are assessed. We then evaluate enthesis tissue replication strategies in terms of their ability to reproduce tissue heterogeneity and fulfill specific enthesis functions and argue that an important gap has emerged: the optimal design of enthesis replacements has rarely been guided by explicit performance objectives grounded in function. Finally, we propose an investigative protocol to address this gap, using the meniscal enthesis as a candidate model system. We anticipate that this framework will streamline design choices, advance enthesis tissue engineering, and motivate similar function‑driven approaches for other musculoskeletal tissues.