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

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ABSTRACT Rotator cuff tears are common and primarily initiate at the stratified 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 and repair of the structure, composition, and mechanical performance of the injured tendon-to-bone enthesis using an innovative stratified biomaterial. Intraoperative 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 and regenerative activity of bioactive MSCs across the injury site. We will evaluate the design of an innovative stratified biomaterial to provide mechanical and trophic stimuli to promote MSC retention and enthesis regeneration. We have generated rigorous proof-of-principle data for a collagen biomaterial that contains bone- and tendon-mimetic scaffold compartments linked with a continuous hydrogel interface. We will show the hydrogel interface inhibits strain concentrations that typically form between biomaterials with mismatched mechanical properties under load. Further, the hydrogel interface provides a site to accelerate fibrocartilage- like differentiation and remodeling in response to trophic factors produced in adjacent tendon- and bone- mimetic scaffold compartments. Taken together, we hypothesize inclusion of a continuous hydrogel zone linking tendon- and bone-specific scaffold compartments provides mechanical and trophic advantages to accelerate regenerative potency versus monolithic and conventional stratified biomaterials. To address our hypothesis we will first determine if and how a mechanically-optimized hydrogel insertion both increases mechanical performance and supports fibrocartilage differentiation in vitro (Aim 1). We will subsequently demonstrate trophic factors produced across the stratified biomaterial accelerate enthesis-specific MSC differentiation and matrix remodeling in vitro (Aim 2). We will ultimately evaluate functional repair and regeneration of the rat rotator cuff enthesis using an enthesis biomaterial-MSC construct in vivo (Aim 3). We will use in vitro cyclic strain bioreactor studies to optimize MSC-biomaterial interactions, then a tiered set of in vivo rat rotator cuff injury models to benchmark the quality and kinetics of enthesis regeneration via cellular, tissue morphology, and mechanical metrics. This project will provide essential insight to aid clinical translation of a biomaterial therapy to improve musculoskeletal enthesis regeneration.