*This proposal describes an innovative protein drug delivery solution to the problem of ?frozen shoulder?, or shoulder arthrofibrosis. Shoulder arthrofibrosis occurs in 9 million individuals in the United States with more than 1.6 million seeking medical care each year. Current treatment options, including intra-articular corticosteroid injections, NSAIDs, and nerve blockers, provide only marginal and temporary relief of patient symptoms and do not address the underlying cause of the disease ? the accumulation of fibrotic collagenous tissue. Surgical interventions are used in more severe cases, but these procedures are fraught with complications and can further aggravate the condition. Our solution is the local intra-articular delivery of human relaxin-2, a 6-kDa reproductive hormone peptide that induces softening of the cervix and is upregulated naturally prior to childbirth. Repurposing this peptide therapeutic for the treatment of arthrofibrosis provides an unprecedented opportunity to treat this disease with a first-of-its-kind therapy and a resulting paradigm shift in the treatment of shoulder arthrofibrosis. We describe relaxin-2 loaded microparticles prepared from both novel and well-established biocompatible and biodegradable polymers for the controlled, sustained release of relaxin- 2 after a single intra-articular administration. The proposed experiments will test the hypothesis that relaxin- 2 will reduce fibrosis in an in vivo shoulder joint contracture immobilization model by inhibiting TGF-?1 signaling via the NO-sGC-cGMP pathway, thereby decreasing joint stiffness and increasing range of motion (ROM). Further, we hypothesize that sustained release of relaxin-2 from a single intra-articular injection of relaxin-2 loaded polymeric microparticles will alleviate the symptoms and causes of arthrofibrosis. Importantly, preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address the hypotheses.
The specific aims of this five-year proposal are:
Aim 1. Determine the mechanism of action (MOA) by which relaxin-2 restores ROM and reduces shoulder contracture, which are hallmarks of shoulder arthrofibrosis;
Aim 2. Optimize the release kinetics of human relaxin-2 from biodegradable and biocompatible polymeric microparticles to afford sustained 6-week delivery after a single local intra-articular administration; and, Aim 3. Evaluate the pharmacokinetics and efficacy of the optimal human relaxin-2 loaded microparticle formulation in an in vivo model of shoulder contracture.
Frozen shoulder, or ?shoulder arthrofibrosis?, is a painful and gradual loss of shoulder motion caused by trauma, surgical procedures, inflammation, or prolonged joint immobilization. Current non-surgical and surgical treatment options for patients are limited in scope and effectiveness with a significant number of patients never regaining full joint function. The sustained delivery of a protein therapeutic (relaxin-2) is described as a novel solution to reduce shoulder contracture and to restore the range of motion.