Engineering Biomaterial-Based Therapies for Improved Lymphatic Function and the Resolution of Chronic Inflammation in Posttraumatic Osteoarthritis
Abstract
Objectives and Rationale: Osteoarthritis is a debilitating condition and is a significant socioeconomic burden in the general, military, and Veteran populations, costing the US economy over $60 billion per year. Current treatments for osteoarthritis either involve invasive surgical procedures or pharmacological intervention primarily for pain relief; however, effective pain relief for osteoarthritis is limited, and remarkably, no disease-modifying drugs are currently US Food and Drug Administration (FDA) approved. Thus, we propose to test novel therapeutics to resolve inflammation in the disease joint and thereby treat osteoarthritis. The overall objective of this proposal is to develop biomaterial-based therapies that can be integrated with imaging modalities to both: (1) elucidate the role of lymphatic function in normal and diseased osteoarthritic joints and (2) promote joint clearance and the resolution of chronic inflammation by delivering inflammation-resolving lipid mediators using controlled-release nanoparticles. Our central hypothesis is that lymphatic function is a critical component in osteoarthritis progression and regenerative therapies that improve lymphatic function and the resolution of chronic inflammation will attenuate disease development and progression. We provide evidence that intra-articular injections of biomaterial-engineered nanoparticles containing resolvins attenuate osteoarthritis disease development. We propose to validate investigate the effects of resolvins treatment on resolution of inflammation and lymphatic dysfunction and extend these therapeutics to late-stage treatment of osteoarthritis. Ultimate Applicability: In this proposal, we uniquely couple novel imaging modalities with preclinical osteoarthritis models to characterize the role of lymphatic function and transport from the knee space during osteoarthritis development and progression. Results from this work could provide a paradigm shift in the role of lymphatic drainage in the etiology of osteoarthritis and provide improved understanding on how particles and drugs can have enhanced retention within the joint. We will also establish a new line of resolvin-based therapeutics that target the transport microenvironment of the joint and the resolution of inflammation. Additionally, by establishing the importance of lymphatic clearance in the etiology of early onset disease, future work could easily adapt these functional biomaterial-based imaging probes to work with more readily available clinical imaging modalities. Ultimately, the results from this work could have a large clinical impact on treatment of osteoarthritis and other diseases associated with chronic inflammation. Project Timeline: A small animal model for osteoarthritis will be used to validate localized delivery of controlled, sustained-release formulation of novel therapeutics to the disease joint. This study will be performed within 3 years, starting from the fabrication of nanobiomaterials for enhanced drug delivery to treatment of late-stage osteoarthritis in a preclinical animal model. Success of this proposal will provide compelling evidence to advance the study into large animal osteoarthritis models and eventually into clinical trials. Military Benefit: Recent analyses of the impact of battlefield injuries showed that post-traumatic osteoarthritis, associated with extremity injuries, is a highly prevalent cause of functional impairment in wounded Soldiers — traumatic knee injuries increase the risk of osteoarthritis at least 10-fold. The incidence of osteoarthritis is 26% higher in military Service personnel compared to the general population for 20 to 24-year-olds and over twice as high in the military population after age 40. As military personnel matriculate into the Department of Veterans Affairs (VA) system, the incidence of arthritis continues to increase. Arthritis is the third most prevalent health problem in the Veteran populat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810505
Entities
People
- Nick Willett
Organizations
- Emory University
- United States Army