Biopolymer-based intra-articular delivery of DKK1 into the contracted rabbit knee

Post-traumatic joint contractures reduce range of motion and require surgical intervention. Repeated surgical interventions can also cause recurrent contractures, leading to a paradox that highlights the need for alternative treatment strategies. Gene expression analysis by next generation sequencing of RNA (RNA-seq) from joint tissues revealed that Wnt ligands are actively expressed in joint capsules. Therefore, we investigated the intra-articular surgical implantation of an inhibitor of fibrotic cell differentiation as a possible strategy for treating post-traumatic joint contracture. Wnt/β-catenin signaling pathway inhibitor Dickkopf 1 (DKK1) was administered into rabbit knees using oligo[(poly(ethylene glycol) fumarate)] hydrogels (OPF). In vitro experiments were used to determine the cytotoxicity of DKK1 and appropriate dosing. Contractures were induced in skeletally mature female rabbits (n = 12) by disrupting knee joint capsules and immobilizing the joint by internal k-wire fixation. Surgical release was performed at 8 weeks when OPF containing DKK1 (or vehicle) was administered. In vitro results indicated that > 90% of DKK1 was released from OPF after 4 days, and rabbit fibroblasts remained viable at 200 nM (DKK1). Although not statistically significant, joint stiffness measurements were different (p < 0.15) among groups (3.0 N·cm/° ± 1.13 for control and 2.40 N·cm/° ± 0.62 for DKK1 animals), which may be clinically relevant. Altogether, our study demonstrates feasibility of this drug delivery method (OPF + DKK1) and provides preliminary safety data for further assessment of this inhibitor of fibrosis. Further mechanistic characterization of post-traumatic joint contractures (and additional therapeutic reagents that deregulate fibrosis) will permit development of adjuvant therapies that increase joint range of motion and reduce joint stiffness: strategies easily tested using our rabbit model and hydrogel-based delivery system.