Bioresponsive microspheres for on-demand delivery of anti-inflammatory cytokines for articular cartilage repair

Osteoarthritis (OA) is a degenerative disease that affects whole joints and usually presents with inflammation and tissue breakdown in affected joints. It is a major cause of disability in adults globally. Although the cause is unclear, it is believed that the stimulation of the natural immune receptors and subsequent inflammatory events resulting from cartilage damage is primarily responsible for the disease. Different treatment options have been proposed to slow the cartilage damage observed in OA. These include anti-inflammatory cytokines, extracellular matrix constituents, immunomodulatory stem cells, chondroprotective drugs, and growth factors. However, treatment options that reduce inflammation appear to be the most effective in preventing further cartilage damage.

IL-4, IL-10, and IL-13 are anti-inflammatory cytokines observed to have the capacity to suppress inflammation and stimulate a metabolic response that protects chondrocytes. Therefore, it has been proposed to use anti-inflammatory cytokines in the treatment of OA because they can be used at almost all stages of the disease; they are safe and will result in quick recovery of damaged cartilage. However, their therapeutic efficacy is limited by their short half-lives in physiological conditions. Thus, to improve the residence time of the cytokines in the joint and therefore enhance their efficacy, anti-inflammatory cytokines ideally require a suitable drug delivery vehicle. Although several materials have been tested for drug delivery to the joint, there has not been much of clinical translation.

In a recently published research in Journal of Biomedical Materials Research, Eunjae Park, Jan P. Stegemann, Dr. Ramkumar T. Annamalai from the Department of Biomedical Engineering at the University of Michigan in collaboration with Dr.  Melanie L. Hart and Professor Bernd Rolauffs at Albert-Ludwigs-University of Freiburg in Germany developed an innovative microsphere drug delivery system that would synchronize the inflammatory response with drug release and reduce the washout of drugs when disease activity is low. Their results demonstrated that the delivery of anti-inflammatory cytokines from gelatin microspheres caused a significant reduction in the severity of the inflammation of IL-1β and lipopolysaccharide (LPS)-activated chondrocytes.

The authors developed their microspheres system from gelatin crosslinked by genipin. In their studies, they attempted to simulate the inflammatory microenvironment found in OA by activating the chondrocytes with inflammatory cytokines and endotoxin. Then they treated the activated chondrocytes with their IL-4, IL-10, or IL-13 loaded microspheres.

By measuring the levels of nitric oxide produced by the chondrocytes as an indicator of inflammation, the research team found that IL-4 and IL-13 released from the microspheres caused a reduction in chondrocyte inflammation by 65–80%. However, with IL-10 loaded microspheres, only a slight reduction in nitric oxide production was observed. This was attributed to the fact that the anti-inflammatory activity of IL-10 is activated primarily in response to that of other anti-inflammatory cytokines. They also found that the anti-inflammatory cytokines delivered by microspheres performed better than when administered as a bolus treatment.

In a nutshell, Dr. Ramkumar T. Annamalai and his colleagues were able to demonstrate that these bioresponsive microspheres are an effective drug delivery vehicle and tool for the treatment of OA and the associated cartilage damage. Microspheres system promise to provide a minimally invasive mode of drug delivery that is localized and prevents unwanted systemic adverse effects. Moreover, the microsphere delivery system regulates drug release based on inflammatory response and they are biodegradable. Future clinical development to advance the bioresponsive microsphere system will provide a new treatment option for patients with OA.