Osteoarthritis (OA) is the most common disease of the synovial joints of the hands, knees, and hips. OA is characterized by damage to the articular cartilage, underlying bone, and chronic inflammation of the joint tissues, leading to the progressive loss of joint function, increased disability, and reduced quality of life. The current standard of treatment for OA is: rehabilitation to maintain joint mobility, palliative treatment to manage pain, and eventually joint replacement surgery for late stage disease. Blood vessels and lymphatics play a critical role in joint maintenance and could potentially affect OA development, progression, therapies, and rehabilitation; therefore, it is necessary to understand clearance mechanisms under normal and diseased conditions.
In collaboration with Dr. Nick Willett at Emory, We have established techniques to measure clearance in rat knee joints using near infrared imaging (NIR), quantitatively assessed cartilage degradation in a clinically relevant rat model of OA via equilibrium partitioning of an ionic contrast agent computed tomography (EPIC-µCT) and use biomaterial scaffolds to study lymphangiogenesis ex vivo. Using these techniques, we will investigate the role of the lymphatic system in the progression of OA and target lymphatics as a therapeutic intervention. Our objective will be achieved by testing our central hypothesis in the following aims.
- Quantify microvascular clearance in naïve rat joints: Particle size is known to play a role in the preferential route of clearance from the knee space. We have shown that clearance of smaller NIR polyethylene glycol (PEG) tracers (~1nm diameter) will be cleared from the joint space primarily via venule mediated clearance while clearance of larger tracers (<10nm) will be cleared from the joint space via lymphatic mediated clearance.
- Determining how OA affects lymphatic function: OA will be induced via our clinically relevant rat model of OA induced via medial meniscus transection (MMT) surgery and we will assess lymphatic function and joint damage. OA severity will be assessed longitudinally via NIR tracer clearance and at endpoint via EPIC-µCT, histology and IHC. To assess how lymphatic injury influences joint health we will develop a model of knee joint collecting lymphatic injury and assess joint health via NIR imaging and joint histology.
- Optimizing a biomaterial platform for testing the effect of soluble and genetic factors on lymphangiogenesis: Rationally designed polyethylene glycol (PEG) hydrogels have been used to support lymphangiogenesis and angiogenesis in vitro and in vivo. We will use this platform to study how cytokines involved in OA progression may affect angiogenesis. Additionally, the downregulation of endothelial epsins, endocytic adaptor proteins which universally regulate vascular endothelial growth factor (VEGF) signaling, has been shown to produce increased expression of VEGF receptors in a murine model where epsins are genetically deleted. Lymphangiogenesis will be investigated ex vivo by encapsulating murine vessel segments in PEG hydrogels and quantifying sprout length, sprout tortuosity, and cell viability under various soluble factors and genotypes.
Contact: Fabrice Bernard