Intra-articular Clearance of Silk Microparticles and Macromolecules in Healthy and Arthritic Rat Knee Joints

Abstract

Osteoarthritis (OA) is a degenerative disease of articular joints characterized by progressive deterioration of the cartilage lining, subchondral bone destruction and thickening of the joint capsule. These tissue changes lead to symptomatic joint pain and joint dysfunction, leading to restrictions on daily life activities. Intra-articular injections of corticosteroids or anti-inflammatory compounds are commonly given to relieve symptoms associated with OA; however, rapid clearance of these compounds from the joint space and into draining synovial lymphatics necessitates the use of drug carriers to increase drug residence and efficacy. Silk fibroin, a protein polymer from the mulberry silkworm (Bombyx mori) and of slow biodegradation in vivo, has a long history of clinical use. Silk fibroin can be fabricated into nano- and micro-particles capable of entrapping small-molecule drugs to provide for sustained release. For this work, silk microparticles were fabricated entrapping the near-infrared fluorescent dye, Cy7, as a model small-molecule drug. The release kinetics of the Cy7 from the silk microparticles were characterized in vitro and fluorescence in vivo imaging was used to study the clearance of silk microparticles following intra-articular injection in healthy rat knee joints.Furthermore, a surgically-induced model of OA was used in rat knee joints to study the effect of OA pathology on intra-articular clearance. Fluorescently-labeled dextrans of varying size (10 and 500 kDa molecular weight) were intra-articularly injected in the knee joints of healthy and OA rats, and fluorescence in vivo imaging was employed to detect changes in the intra-articular clearance. Additionally, a new method to characterize the trans-synovial clearance of the fluorescent dextrans was developed using the confocal microscopy of joint tissue sections from healthy and OA joints.