Developing Progranulin-Loaded Protein-Engineered Hydrogel for Post-Traumatic Osteoarthritis
Abstract
Post-trauma osteoarthritis (PTOA) results from degradation of cartilage induced by joint injury. Cartilage is an avascular (without blood supply) tissue and thus relies on external stimuli to repair and heal itself. In fact, osteoarthritis (OA) is the most common cause for early retirement or relief from active duty in military service. Currently, there is no cure for this disease. We recently discovered progranulin (PGRN) as a naturally occurring inhibitor of TNF, a master regulator of inflammation (Tang, et al, Science, 2011). This work drew much attention because of the potential application of PGRN to treat various TNF-related diseases and conditions. This discovery was highlighted by numerous leading academic journals, including a Perspective in Science (Wu H, Siegel RM, 2011); Research Highlights in Nature Medicine (Silva KD, 2011), Nature Review Drug Discovery (Crunkhorn S, 2011), and Nature Review Rheumatology (Price S, 2011); a cover story in Nature SciBX (Martz, L. 2011); a Podcast in Science Signaling (VanHook AM, 2011); and a lab report in JAMA (Hampton T, 2011). The discovery was also reported by mass media, including radio, newspapers, and periodicals. For instance, Technology Review and Science Daily published full stories on this finding. In addition to its anti-TNF activity, we also found that PGRN is novel chondroprotective growth factor, because intra-articular injection of recombinant PGRN prevents PTOA in a mouse model. More importantly, we have developed a PGRN-derived engineered protein, Atsttrin, which is much smaller than PGRN but more effective than PGRN in treating inflammatory arthritis. Another group very recently demonstrated that Atsttrin ameliorated OA development. In this grant application, we will deliver PGRN and the PGRN derivative Atsttrin into a rabbit PTOA model by using a thermosensitive protein-engineered hydrogel. A thermosensitive linker will enable in situ gelation of the hydrogel, making its application a minimally invasive procedure. The proposed construct is designed to synergize the anti-inflammatory and cartilage-protective effects of PGRN/Atsttrin and EC hydrogel to increase the quality and the rate of cartilage healing. Given that the construct is injectable, it is easy to administer in areas with limited resources, such as the combat field. The overall objective of this study is to engineer a tissue engineering construct that can prevent cartilage destruction and increase cartilage regeneration in joint injury and PTOA. The successful completion of this project will provide a minimal invasive prevention and treatment for PTOA and other combat-related joint injuries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610483
Entities
People
- Jin K Montclare
Organizations
- New York University
- United States Army