INTEGRATIVE DEVICE FOR TREATING ROTATOR CUFF TENDON INJURIES

Background: This application focuses on the challenge of tendon-to-bone integration for rotator cuff repair and augmentation. Rotator cuff tears represent the most common shoulder injury, with over 500,000 repair procedures performed annually in the United States. Moreover, the incidence of shoulder injuries among military personnel is more than double that of the general population. Due to the inability of existing grafts to sustain physiologic levels of loading and promote biologic healing of tendon to bone post-surgical repair, there exists an unmet demand for integrative fixation devices for rotator cuff repair. Our approach centers on the regeneration of the anatomic insertion site between tendon and bone, which consists of distinct yet continuous non-calcified and calcified fibrocartilage regions. This research is relevant for the fourth and fifth Translational Research Award Focus Areas, which center on 'research on treatment of non-battle orthopaedic injuries' and 'research toward osseointegration of upper extremity prostheses.'Objective and Hypothesis: The objective of the proposed project is to facilitate tendon and bone integration in vivo by focusing on the regeneration of a physiologically relevant interface between these tissues. Our approach is guided by the working hypothesis that functional tendon-to-bone fixation can be achieved and expedited by strategically mimicking the structure-function properties of the native interface and harnessing mesenchymal stem cells (MSCs) and select interface-relevant growth factors (transforming growth factor [TGF]-beta3). To test this hypothesis, this proposal has two specific aims.Aim 1: In Vitro Optimization of Interface Scaffold for Tendon-to-Bone Integration (Years 1, 2).Task 1: Determine the optimal MSC seeding density that promotes cell growth and matrix deposition.Task 2: Determine the effects of fiber diameter on MSC growth and biosynthesis on scaffold.Task 3: Evaluate the controlled release of TGF-beta3 for MSC-mediated fibrocartilage regeneration on interface scaffold, focusing on the effects of growth factor dose and culture time.Aim 2: In Vivo Testing of Optimized Biphasic Scaffold for Functional Tendon-to-Bone Fixation (Years 2, 3).Task 1: Evaluate tendon-to-bone interface regeneration after scaffold repair in a sheep shoulder model.Task 2: Evaluate the tendon and tendon-to-bone insertion site mechanical properties post-repair in sheep.Study Design: Inspired by the organization and mineral distribution at the native tendon-to-bone interface, we have engineered an aligned nanofiber-based biphasic scaffold. Phase A of this scaffold consists of a polylactide-co-glycolide (PLGA) nanofiber mesh for the formation of the non-calcified interface region, while Phase B is made up of composite PLGA and hydroxyapatite nanofibers designed for the formation of the calcified region. The efficacy of this scaffold for interface regeneration was previously demonstrated in a small animal model. Thus, the next step is to expedite tendon-to-bone healing by harnessing stem cells and controlled TGF-beta3 delivery and to further refine the stratified scaffold design for testing in a large animal model. First, the optimal stem cell seeding density will be determined. Next, modulation of nanofiber diameter and controlled TGF-beta3 delivery are expected to enhance MSC-mediated interface regeneration both in vitro and in vivo. Finally, to bring this novel technology closer to clinical translation, we will test the optimized scaffold in a sheep model.Translation: The clinical translation potential of the proposed scaffold has been recognized by the BioAccelerate NYC prize (declined) and Columbia-Coulter Translational Partnership grant (no overlap). The relative simplicity of the scaffold design, ease in surgical implementation, and lack of alternatives have fueled interest in this novel technology. Funding of the proposed project will enable us to conduct large animal studies and move the project to the next stage of clinical translation and Food and Drug Administration approval.Military Benefit: Debilitating musculoskeletal injuries are frequently sustained during routine service and training. However, current treatment strategies are not adequate to restore full joint motion and mobility. Restoring tendon-to-bone integration is especially critical for military personnel given the high incidence of injuries in a relatively young patient population and their significantly higher functional demands. Consequently, there is a tremendous need for soft tissue grafts that promote the functional fixation of tendon to bone. Moreover, it is anticipated that findings from these proposed studies will also aid the regeneration of complex tissue systems and ultimately enable total joint and limb regeneration.