Ruthenium carbene-catalyzed ring opening metathesis polymerization (ROMP) is a reliable and efficient method to synthesize well-defined polymers with relatively low polydispersities. These polymers, mostly synthesized from norbornenes and cyclopentadienes, are of wide-spread interest since diverse functionalities and architectures can be prepared. For pharmaceutical applications, chemotherapeutic or antibacterial agents are tethered to create bioactive polymers. An unexplored area is the design of functional medical devices based on the macroscopic or bulk properties of these polymers. Preliminary investigations revealed that large molecular weight polymers of poly(7-oxanorbornene-2 carboxylate) in aqueous solution were lubricious and can lubricate ex vivo osteoarthritic cartilage surfaces (J. Am. Chem. Soc. 2013, 135, 4930-4933). Importantly, we have preliminary data demonstrating that these polymers: 1) function to lower the coefficients of friction in ex vivo bovine and human articular cartilage plug models compared to saline or hyaluronic acid viscosupplements (e.g. Synvisc-One(R)), and perform similar to healthy synovial fluid;2) exhibit no in vitro or in vivo toxicity;and 3) resist degradation by hyaluronidase, therby enabling prolonged synovial joint residence time after intra-articular injection. Building on these results, we hypothesized that these polymers may have efficacy as a synthetic bio lubricant by reducing the friction and minimizing the wear between two cartilage surfaces. We propose the following three specific aims to support this hypothesis:
Aim 1 : Determine the dependence of polymer architecture, molecular weight, rigidity, and charge on the rheological and lubricating properties using both metal-on-metal and ex vivo bovine cartilage plug models of articulating joint surfaces;
Aim 2 : Determine the performance and lubrication mechanism of the bio lubricant in ex vivo healthy and traumatized / osteoarthritic human metacarpal phalangeal joints (MCPJs;index finger) to evaluate function in a discrete synovial joint;
and Aim 3 : Determine the performance and chondroprotective capability of the biolubricant in vivo using a trauma-induced osteoarthritis rabbit model. Successful completion of these studies will result in: 1) the development of structure-activity relationships and design requirements for highly effective biolubricants for cartilage surfaces;2) insight as to mechanism of lubrication for these polymers in contact with articular cartilage vs. conventional metal surface;and 3) ex vivo and in vivo performance data in healthy and osteoarthritic cartilage joints. The next steps in the translation of this technology to the clinic will involve good manufacturing practice synthesis, a large animal model study of traumatic osteoarthritis, FDA required biocompatibility testing, and biodistribution/pharmacokinetic studies. The lead PI has previous experience and success in translating a polymeric medical device to the clinic.
The objective of this proposal is to evaluate a series of new polymers as lubricants for the treatment of osteoarthritis (OA). As a lubricant, the polymer will reduce the wear at the cartilage-cartilage interface thereby preventing further cartilage tissue damage. The proposed mechanistic and translational studies will evaluate the polymer in a human cadaver finger model as well as a rabbit model of traumatic OA. This innovative treatment will be of interest to the more than 20 million individuals in the U.S.A. who suffer from OA.
|Lakin, B A; Ellis, D J; Shelofsky, J S et al. (2015) Contrast-enhanced CT facilitates rapid, non-destructive assessment of cartilage and bone properties of the human metacarpal. Osteoarthritis Cartilage 23:2158-2166|