Assessing the Impact of Patient Factors on Therapeutic Capabilities of BMAC for Osteoarthritic Pain

Post-traumatic osteoarthritis (PTOA) is a debilitating condition of articular joints that is associated with pain, loss of activity, and reduced quality of life. Non-battle musculoskeletal injuries in active Military members are higher than civilian counterparts. Due in part to this increased risk of traumatic injury, and the occupational demands of high-impact repetitive joint use, osteoarthritis incidence is almost three times higher in the military vs civilian population by the age of 40. Current options (platelet-rich plasma, hyaluronic acid) for joint preservation are being gradually replaced by autologous cell-based injections, including bone marrow aspirate concentrate (BMAC), that aim to reduce intra-articular inflammation and relieve pain. Limitations for autologous sources of BMAC expose these therapies to donor variation in product and efficacy. Age and PTOA can alter the cellular composition and function of bone marrow, though how these changes may affect efficacy of BMAC injections for PTOA pain relief remains unknown. In this proposed project, we seek to devise a strategy to facilitate pain relief and joint preservation with BMAC injections in a preclinical model of PTOA. Our central hypothesis posits that donor age, sex, and PTOA status impact BMAC efficacy in relieving osteoarthritic pain and that personalized regimens of endurance exercise could prime bone marrow to become a potent immunomodulatory product. We will address this objective with two specific aims: 1) Determine the effect of patient factors (age, sex, PTOA) and exercise on BMAC composition and immune-modulatory potential; 2) Evaluate the potential of individualized pre-habilitation to increase the pain- relieving and joint-preserving capabilities of BMAC. In the first aim, we will harvest and evaluate BMAC from 3 mo and 12 mo male and female Lewis rat populations with and without induced PTOA. We will exercise a subset of rats daily. We will characterize the cellular composition and immune-modulatory capabilities of the BMAC from all donors. We will then directly compare BMAC quality from young vs. middle-aged, and osteoarthritic rats and evaluate whether exercise can rejuvenate BMAC immune-modulatory potential. In the second aim, we will test the efficacy of these BMAC products in vivo using a preclinical model of PTOA. We will assess longitudinal pain and function, as well as end-stage inflammation and tissue health. We will then link the compositional and functional changes of BMAC due to age, sex, PTOA, and exercise to in vivo pain relief. Findings from the successful completion of these aims will be well positioned for expedited clinical translation to establish guidelines for quality control of BMAC and to encourage clinicians to implement pre-habilitative interventions.