A rabbit model demonstrates the influence of cartilage thickness on intra‐articular drug delivery and retention within cartilage

Abstract

For evaluation of new approaches to drug delivery into cartilage, the choice of an animal model is critically important. Since cartilage thickness varies with animal size, different levels of drug uptake, transport and retention should be expected. Simple intra-articular injection can require very high drug doses to achieve a concentration gradient high enough for drug diffusion into cartilage. New approaches involve nanoparticle delivery of functionalized drugs directly into cartilage; however, diffusion-binding kinetics proceeds as the square of cartilage thickness. In this study, we demonstrate the necessity of using larger animals for sustained intra-cartilage delivery and retention, exemplified by intra-articular injection of Avidin (drug-carrier) into rabbits and compared to rats in vivo. Penetration and retention of Avidin within cartilage is greatly enhanced by electrostatic interactions. Medial tibial cartilage was the thickest of rabbit cartilages, which generated the longest intra-cartilage half-life of Avidin (t 1/2 ¼ 154 h). In contrast, Avidin half-life in thinner rat cartilage was 5-6 times shorter (t 1/2 $ 29 h). While a weak correlation (R 2 ¼ 0.43) was found between Avidin halflives and rabbit tissue GAG concentrations, this correlation improved dramatically (R 2 ¼ 0.96) when normalized to the square of cartilage thickness, consistent with the importance of cartilage thickness to evaluation of drug delivery and retention. ß

Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis

“…Due to the unanticipated closure of this vendor during the study, the final ten rabbits were ordered from an alternate vendor, Covance Research Products (Denver, PA, USA). The thickness of rabbit tibial cartilage was measured to be between 350–550 μm (Bajpayee et al , 2015), consistent with previously reported data (Hoch et al , 1983). Generally, by 8 months of age, the growth plates in the distal femur and proximal tibia are closed, thereby defining skeletal maturity (Hunziker et al , 2007; Masoud et al , 1986).…”

“…The residence time for avidin (and other solutes) in cartilage is proportional to the square of cartilage thickness (Bajpayee et al , 2015). Since cartilage thickness is related to joint size, the use of animals larger than mice or rats is important for generating intra-cartilage drug residence times that more closely approximate what would occur in humans.…”

“…Based on the fact that there is about 1 mL of synovial fluid in the inflamed rabbit joint and ~35–40 % of IA injected avidin is retained inside the joint after 24 h (Bajpayee et al , 2015), a total of 0.15 mg of Dex is needed to achieve a 100 μM concentration inside the rabbit joint 24 h after IA injection. The glucocorticoid dose recommended for small animals, such as cats and dogs, is 0.5 mg per 5 kg weight.…”

“…While these drug carriers can be useful in providing extended pain and inflammation relief through enhanced delivery to targets in the synovium, preclinical and clinical studies strongly suggest that certain DMOADs must be delivered to chondrocytes or ECM components to achieve cartilage protection (Chevalier et al , 2009; Cohen et al , 2011). As a first step toward addressing this challenge, avidin, due to its optimal size and positive charge (Bajpayee et al , 2014b), can penetrate the full thickness of rabbit cartilage following intra-articular administration, resulting in an intra-cartilage half-life of about 7 d (Bajpayee et al , 2015). Such cationic proteins and their derivatives offer great potential as carriers for intra-cartilage drug delivery.…”

The great debate: Should Osteoarthritis Research Focus on “Mice” or “Men”?

“…We are bipeds as opposed to quadrupeds, our joint biomechanics and anatomy is distinct, including for example vast differences in the thickness of cartilage compared with species used in pre-clinical research, that likely has important implications for therapeutic development 12 . Similarly during evolution the human brain underwent extraordinary development, and along with that the arguably unique perception of self and complex cognitive capabilities and social interactions.…”