Injectable Fibrous Scaffolds for Meniscal Repair

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Project Summary/Abstract The meniscus is an important load-bearing structure that protects the underlying articular cartilage and thus reduces the incidence of osteoarthritis (OA). Unfortunately, it has limited healing capacity in adults, so tears often require surgical treatment. Current treatments include partial meniscectomy; however, removing part of the meniscus exposes the cartilage and the extent of removal correlates with the magnitude of cartilage degeneration. Unlike adult menisci, fetal and juvenile menisci exhibit intrinsic repair, which reduces the rate at which children present with meniscus tears. Thus, tissue engineering approaches that recapitulate features of younger menisci may provide novel approaches to treating meniscus tears. Multi-fiber scaffolds, whose porosities are tailored to mimic low density fetal extracellular matrices (ECM), have previously been developed that deliver multiple factors to promote initial healing. However, these rigid electrospun scaffolds have reduced control over individual fiber components and cannot be delivered arthroscopically. This proposal targets these impediments by utilizing a post-processing strategy in which a scaffold is fabricated out of fragmented fibers that can be injected into a defect, reconstructed after injection, and stabilized with light. By combining different fiber populations, this assembly permits the individual tuning of various released factors by way of tuning different fiber degradation rates. The proposed scaffold will release a nuclear softening agent (Trichostatin A ‘TSA’) over several days, further mimicking the softer nuclei of fetal menisci compared to adult, and a chemotactic agent (connective tissue growth factor, CTGF) over several weeks. These two factors are expected to synergistically promote cell infiltration and ECM deposition into the scaffold. To demonstrate the translational capacity of this material, three Aims will be conducted. Aim 1 will be geared towards fabricating the material and demonstrating scaffold biofactor release activity individually and when released simultaneously in vitro. Scaffold fiber components will be tailored to have precisely tuned kinetics. Aim 2A will demonstrate the efficacy of the developed fragmented multi-fiber assembly (FMA) in a subcutaneous rat model, thus confirming that the factors released continue to promote cell migration and ECM deposition within an in vivo environment. Aim 2B will involve insertion of the FMA into a meniscus defect site in Yucatan minipigs. This large animal pilot study will demonstrate that the designed material stays within its injection site and that it integrates with the surrounding meniscus on a cellular level. Thus, this sub-Aim will set the framework for future studies assessing the efficacy of this and other proposed tissue engineering approaches in a large animal model of meniscus tears. Successful completion of these Aims will bypass current impediments to implementing fibrous scaffolds clinically, thus providing an alternative treatment option for repairing the meniscus.