Biomimetic approaches for enthesis tissue engineering

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ABSTRACT Rotator cuff tears are prevalent, particularly in the elderly population, and typically require surgical repair to regain shoulder function. Unfortunately, successful repair remains a major clinical challenge, with high post- operative failure rates. At the root of these failures is poor healing at the repaired tendon-to-bone interface, which does not regenerate the native tendon enthesis attachment structures. Specifically, the healthy tendon enthesis consists of a transitional tissue with spatial gradations in composition (e.g., mineral content) and cell phenotype (e.g., tenocytes, chondrocytes, and osteoblasts), which provides a strong and tough attachment to transfer muscle load from tendon to bone. To address the critical clinical need to improve outcomes after tendon-to-bone repair, this project brings together a multidisciplinary research team to develop, validate, and translate a novel class of biomimetic scaffolds for enhancing healing. The team is led by Dr. Thomopoulos (MPI, an expert in tendon-to-bone development, pathology, and repair) from Orthopedics and Biomedical Engineering at Columbia University and Dr. Xia (MPI, an expert in materials science and nanotechnology) from Biomedical Engineering at Georgia Tech. Key compositional and structural features of the natural tendon-to-bone attachment will be directly fabricated in Aim 1 or generated by stem cells provided with the appropriate cues in Aim 2. The first (acellular) approach has the benefit of high throughput and off-the-shelf availability whereas the second (cellular) approach has the advantage of a responsive extracellular matrix generating component. Funnel-shaped microchannels will be laser drilled through the depth of the scaffolds to encourage cell migration and extracellular matrix deposition, and thus alleviate the concern that the interposed scaffold will be a barrier to healing between the tendon and bone. These two designs will be independently fabricated and evaluated in vitro and then tested in a clinically relevant animal model of rotator cuff injury and repair in Aim 3. Reducing the failure rates of rotator cuff surgical repairs will have a major impact on a large population of patients. The proposed clinically relevant translational studies have the potential to directly impact the treatment of rotator cuff injuries. Furthermore, the results will be broadly applicable to connective tissue-to-bone repair in other locations (e.g., ACL reconstruction, meniscal repair).