A Novel Glycosaminoglycan Mimetic Scaffold for Cartilage Repair

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Project Summary With the limited healing capability of articular cartilage, clinical intervention is necessary to prevent further articular cartilage damage and early onset of degenerative osteoarthritis. Current surgical procedures result in inadequate repair suffering from poor integration with surrounding hyaline cartilage and the formation of fibrocartilage instead of normal hyaline cartilage. The most frequently used reparative treatment for small symptomatic lesions of articular cartilage of the knee is microfracturing, where multiple holes are made in the subchondral bone allowing stem cells from the bone marrow to migrate to the joint surface and facilitate repair. However, in the long-term, this method does not result in the replacement of normal hyaline cartilage. The approach described here is to combine the surgical treatment of microfracturing, which will provide endogenous cells capable of chondrogenesis to the defect site, with a novel scaffold that mimics the cartilage extracellular matrix during development to promote chondrogenesis and cartilage tissue formation. During cartilage development, the major matrix components are collagens and proteoglycans, wherein the predominant glycosaminoglycans (GAGs) in the proteoglycans are chondroitin-6-sulfate and heparin sulfate. The pattern and degree of sulfation in these and other GAGs play an integral role in providing the necessary functionality/bioactivity for growth factor interactions in cartilage development. Typical synthetic biomaterials lack functional sites that would enable this interaction. This study will investigate a semi-synthetic derivative of cellulose, which is one of the most abundant natural materials, for cartilage repair. Sodium cellulose sulfate (NaCS), which is water soluble and mimics the structure of GAG, will be fabricated into a scaffold and combined with microfracturing as a novel strategy for cartilage repair. NaCS is a linear polysaccharide that can be synthesized with varying degrees of sulfation for improved bioactivity over native GAGs. In our studies to date, fully sulfated NaCS has shown promise in promoting chondrogenesis and accelerating the repair of osteochondral defects. We hypothesize that NaCS will impart functional qualities that are similar to GAGs, direct chondrogenesis and cartilage tissue formation. Aim 1 will fabricate and characterize NaCS constructs and investigate bone marrow derived mesenchymal stem cell (MSC) chondrogenesis in vitro. Aim 2 will evaluate cartilage tissue formation and integration in vivo. The goal of this aim is to evaluate cartilage tissue formation and integration with surrounding host cartilage in a rabbit defect model. Aim 3 will investigate NaCS constructs in a clinically relevant, critically-sized cartilage defect model. This study proposes a novel GAG-mimetic strategy where NaCS containing scaffolds can be combined with microfracturing as an effective and translatable strategy for treating cartilage lesions.