Stratified and mechanically-tough biomaterial implant to improve tendon-to-bone enthesis regeneration

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ABSTRACT Rotator cuff tears are common and occur most commonly as partial-width injuries within the fibrocartilage interface (enthesis) linking tendon to bone. Surgical reattachment of tendon to bone forms a narrow fibrovascular scar rather than regenerates a continuous fibrocartilage enthesis. The resultant sharp boundary between mechanically mismatched tendon and bone leads to strain concentrations and high rates of re-failure at the enthesis. The objective of this proposal is to guide functional regeneration of the structure, composition, and mechanical performance of the injured tendon-to-bone enthesis using an innovative biomaterial therapy. Local implantation of MSCs at the injury site during surgical repair is an attractive option to accelerate enthesis regeneration. However it is essential to develop a biomaterial carrier to improve retention of bioactive MSCs at the injury site and to provide an optimized microenvironment to spatially-regulate MSC differentiation and fibrocartilage remodeling. We have generated rigorous proof-of-principle data for an innovative biomaterial that contains porous mineralized (bone) and anisotropic (tendon) scaffold compartments linked with a continuous gelatin hydrogel interface. This hydrogel interface inhibits formation of strain concentrations that typically form between biomaterials with mismatched mechanical properties under load. The hydrogel interface also provides a depot to locally pattern morphogens to accelerate MSC fibrocartilage differentiation and matrix remodeling. To address our objective we will first demonstrate a mechanically-optimized hydrogel insertion increases biomaterial toughness and locally promotes fibrocartilage differentiation. We will subsequently establish a fibrocartilage-optimized biomolecule patterning strategy to accelerate enthesis-specific MSC differentiation and matrix remodeling. We will ultimately evaluate functional regeneration of the rat rotator cuff enthesis using an optimized biomaterial-MSC construct. We will use in vitro cyclic strain bioreactor studies to optimize MSC- biomaterial interactions as well as a rigorous in vivo rat rotator cuff injury model to benchmark the quality and kinetics of enthesis regeneration via cellular, tissue morphology, and mechanical metrics. This project addresses critical gaps in knowledge and will validate an innovative biomaterial paradigm to accelerate musculoskeletal enthesis regeneration.