Osteoarthritis (OA) is a major cause of disability throughout the world, and prevalence of OA increases with age. With an aging population, the socioeconomic burden associated with OA is expected to increase over the coming years. The hallmark of this disease is a slow, progressive cartilage erosion driven in part by inflammation from an activated synovium (the tissue that surrounds the joint). Chondrocytes (the cells in cartilage) lose their capacity to maintain a healthy tissue as they become diseased. Macrophages (activated cells in the synovium) contribute to the chondrocyte phenotype shift and subsequent cartilage degradation through the secretion of pro-inflammatory molecules. Currently, there are no effective disease modifying treatments to intervene in this degradative cascade. The ultimate goal of this work is to develop a disease modifying intra- articular (IA) injection treatment which targets diseased chondrocytes and macrophages with one simple approach ? by shifting the cell membrane potential (Vmem) to a more positive (depolarized) state. Vmem depolarization can be achieved with a variety of methods, the easiest of which is through simply increasing the extracellular potassium concentration. However, in order to implement depolarization strategies into a disease modifying IA injection, we first need to demonstrate a proof-of-concept (i.e. that we can return activated, diseased cells to an unactivated state via depolarization) and determine the length, intensity, duration, and specificity of Vmem depolarization treatments. As such, we propose the following two Specific Aims:
Aim 1 : Establish the ability of Vmem depolarization to transition activated, cartilage explants and pro- inflammatory macrophages to a more normal, unactivated phenotype.
Aim 2 : Determine the length, intensity, duration, and specificity of Vmem depolarization treatments appropriate to IA injection approaches.

Public Health Relevance

Despite osteoarthritis being a major cause of disability throughout the world, limited disease modifying treatments are available for patients. The hallmark of this disease is a slow, progressive cartilage erosion driven in part by inflammation from an activated synovium (the tissue that surrounds the joint). We propose to address these two disease processes (cartilage degradation and activated synovium) through developing an intra- articular injection treatment which depolarizes the transmembrane potential of the cells within each tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
5R03AG056168-02
Application #
9660522
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Williams, John
Project Start
2018-03-15
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rensselaer Polytechnic Institute
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180