IA delivery of FIX affords protection from synovitis compared with systemic administration of FIX. FIX ^−/− mice received either IV recombinant hFIX followed by a joint capsular needle puncture injury and NS OR needle puncture with coincident IA injection of hFIX. A group of FIX^−/− mice received no FIX and puncture with normal saline as a concurrently injured negative control (■). Fourteen days after the capsular puncture injury to left hind limb knee joint, left (injured) knee joints were collected for histologic examination using a validated mouse hemophilic synovitis grading system; uninjured (right) knee joints of the mice were also graded (far right column, “FIX^−/− no injury”). A grade of zero to 10 is awarded for increasing pathology based on parameters of synovial hyperplasia (0-3 points), vascularity (0-3 points), or the presence of blood, synovial villus formation, discoloration by hemosiderin, or cartilage erosion (0 = absent; 1 = present). Average scores with the SEM are shown. Differences between IA treatments of 20 IU/kg and 10 IU/kg, compared with 100 IU/kg IV, were statistically significant (P < .001, P < .05, respectively).