To address this problem, an implantable, PLGA-based dosage form providing sustained administration of amobarbital has been developed. The hypothesis is that this strategy can moderate oxidant overproduction over longer timeframes and subsequently block PTOA development following less severe joint trauma. To date, a formulation has been developed which elutes amobarbital at a targeted rate to achieve a localized, therapeutic concentration. Further optimization of the formulation will be conducted. This effort will focus on prolonging the duration of the amobarbital release. This project will culminate in an in vivo proof-of-concept study in a well characterized medial meniscus destabilization rabbit model.

It has been previously shown that mitochondrial damage is caused by overproduction of oxidants and that a single dose of amobarbital, a barbiturate that reversibly inhibits mitochondrial electron transport, blocked oxidant overproduction and mitigated PTOA following an intra-articular fracture. Medial meniscus tears are the most common orthopedic injury concomitant with articular cartilage damage. This injury has been characterized as pathogenic due to chronically elevated mechanical stress which leads to prolonged oxidative stress. Such conditions are unlikely to be countered by a single amobarbital dose.

Articular chondrocytes exposed to excessive mechanical stresses, arising from multiple joint injuries, accumulate defects in mitochondrial function that contribute to the progression of post-traumatic osteoarthritis (PTOA). At present, there are no disease-modifying treatments before terminal joint replacement, and current standard-of-care interventions fail to prevent PTOA in injured joints. Therefore, there is an immediate unmet need for strategies to prevent PTOA following joint trauma.