Use of an isolated joint model to detect early changes induced by intra-articular injection of paclitaxel-impregnated polymeric microspheres

Paclitaxel is a chemotherapeutic agent that suppresses cellular proliferati on and angiogenesis and has been effective in suppressing proliferative syn ovitis in animal models. Local joint delivery of paclitaxel is being pursue d as a treatment for rheumatoid arthritis in humans, to avoid systematic to xicity of the drug. We used an extracorporeal, isolated metacarpophalangeal joint preparation that uniquely permitted the simultaneous evaluation of c odependent hemodynamic, microvascular, and transsynovial flow responses of a joint. Specifically in this study, the isolated joint preparation provide d quantitative assessment of vascular flow, transsynovial flow, and morphol ogic changes in response to intraarticular injection of paclitaxel (50 ng) in poly-(DL)-lactide co-glycolide 50:50 microspheres (50 mum diameter) to a ssess initial intra-articular biocompatibility. Control joints were isolate d but not injected. Serial hemodynamic measurements, transsynovial fluid fo rces, synovial fluid analysis, synovial and capillary permeability, and oxy gen metabolism were measured every 30 min during a subsequent 3-h isolation period. At termination, synovium and cartilage were harvested from bilater al metacarpophalangeal joints for histopathologic assessment. Intra-articul ar injection of this formulation of paclitaxel did not significantly affect hemodynamic parameters in the joint during this short-term study, and earl y joint inflammatory reaction was minimal. However, transsynovial fluid for ces were significantly greater in treated joints as evidenced by greater sy novial fluid flow, intra-articular pressure, transitional microvascular pre ssure, and permeability to fluid transport. Gross and histologic morphology of synovium and articular cartilage were normal in all isolated joints. In conclusion, this extracorporeal in vivo isolated joint model permitted inv estigation of the early changes in joint physiology induced by this microsp here formulation and dose of paclitaxel in joints and could provide a more physiologic and dynamic model for study of the pharmacokinetics of drug abs orption following intra-articular administration. Due to the minimal inflam mation and lack of evidence of gross or histologic change in the joint, thi s formulation of paclitaxel should be adequately biocompatible for use in a n in vivo animal model for further study of its feasibility for human use.