Osteoarthritis is a debilitating disease that affects cartilage and bone in joints. Cartilage injuries, if left untreated, are one of the leading risk factors for developing osteoarthritis. Thus, treating cartilage injuries early may help prevent progression of osteoarthritis. There are however no clinical solutions that are capable of repairing damaged cartilage and replacing it with healthy functional articular cartilage. Thus, the focus of our research program is to develop novel hydrogels that support regeneration leading to full restoration of joint tissue and its function. Towards this goal, we focus on developing hydrogels that support differentiation and tissue growth and have begun to translate our materials in vivo towards the long-term goal of creating a viable clinical solution for cartilage regeneration.
Synthetically-derived hydrogels offer a highly tunable platform to create biomimetic environments that support repair of damaged or diseased cartilage. Our group has worked extensively to identify and create biomimetic, biodegradable, and photopolymerizable hydrogels. Photopolymerization offers the ability to form hydrogels directly in the defect and control gelation time (e.g., ∼ 10 seconds). In developing the chemistry of the biomimetic hydrogel, our research has pointed to the importance of physiochemical cues in directing stem cell differentiation for chondrogenesis and cartilage regeneration. The incorporation of cartilage specific extracellular matrix (ECM) analogs into a synthetic hydrogel combined with dynamic mechanical loading results in a synergistic response that produces a robust differentiation and improves tissue growth. These physiochemical cues appear to be more potent than either chemical or mechanical cues alone. For example, we have incorporated chondroitin sulfate, the main sulfated glycosaminoglycans found in cartilage, into a synthetic hydrogel to mimic cartilage's high fixed charge density. Upon dynamic loading, this creates an environment that induces oscillations in ion flow and leads to dynamic changes in local osmolarity and streaming potentials, both of which can regulate ion channels on the cell membrane. We have also incorporated cell adhesion peptides that enable integrins on encapsulated cells to interact with the hydrogel and which can act as mechanoreceptors. We have found that combining both ECM analogs into a cartilage biomimetic hydrogel improves ECM synthesis capabilities in chondrocytes, but only under dynamic loading. This cartilage biomimetic hydrogel enhances chondrogenesis of mesenchymal stem cells, but under dynamic loading is able to inhibit RunX2, collagen X, and MMP13 activity, which are characteristic markers of a hypertrophic phenotype in cartilage. Thus, this novel cartilage biomimetic hydrogel holds promise for maintaining a stable chondrogenic phenotype and regenerating cartilage within the joint where dynamic mechanical forces are prevalent.
In addition to identifying a local hydrogel environment that supports chondrogenesis and cartilage tissue regeneration, the success of such a therapy requires the translation in vivo. Towards this goal, we have created an in vitro model of a cartilage defect in an osteochondral plug that is subjected to physiological and dynamic compressive loading. When left untreated, the cartilage surrounding the defect undergoes rapid remodeling in four weeks, leading to loss of proteoglycans, increased collagen degradation, and a decrease in mechanical properties; signs of cartilage degeneration and a precursor to osteoarthritis. However, if the defect is filled with a mechanically supportive hydrogel that distributes the loads across the osteochondral plug degeneration could be arrested. Specifically, there was no evidence of proteoglycan loss, minimal collagen degradation, and no change in mechanical properties. Using this novel defect model, we have shown that mechanical loading can have detrimental effects on cartilage injuries if left untreated, but that a mechanically supportive hydrogel can protect the surrounding tissue from further damage.
While our research is still on going, we have identified novel cartilage biomimetic hydrogels that support differentiation and tissue growth. We are currently testing this novel biomimetic, biodegradable, and photopolymerizable hydrogel in a skeletally mature (8 month old) rabbit model with an osteochondral defect. Additionally, we are developing advanced strategies to combine our novel cartilage biomimetic hydrogel with stiff structural features to create mechanically supportive environments the enable tissue growth and protect the surrounding tissue from further degeneration. Our long-term goal is to develop clinically useful technologies that help prevent the onset of osteoarthritis by treating cartilage injuries early and restoring normal function.
Disclosure of Interest S. Bryant Grant/research support from: NIH and NSF
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