Core-shell polymer microspheres with poly(d,l-lactic-co-glycolic acid) (PLGA) core and poly(l-lactic acid) (PLLA) shell were developed for sustained release of bupivacaine for postoperative pain relief after knee surgery. The PLLA-rich shell acted as a diffusion barrier, allowing linear release of bupivacaine in a goat model over an extended period of 2 weeks post-surgery. In vivo bupivacaine concentrations in the goat synovial fluid remained within therapeutic levels for the 2 weeks, whereas bupivacaine concentrations in the blood plasma remained safely below toxic levels. All animals survived until the end of the 28 day study, with no inflammation, infection or reduced mobility. Explantation at day 28 revealed some soft microsphere remnants in the para-patellar space of the knee joint. However, there was no damage to the articular surfaces, or interference with joint motion. Histological analysis of each knee compartment did not reveal any signs of osteoarthrosis or degeneration within the joints, and safranin-O staining showed intact cartilage surfaces with well-preserved proteoglycan content.
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