Chronic joint pain, swelling, and limited mobility are an everyday occurrence for the 3 out of 10 Americans older than 65 who have osteoarthritis. Although there are ways to manage the symptoms – we have all seen the arthritis pain medication advertisements – osteoarthritis remains an incurable disease.
Problems usually start in later years as a consequence of wear and tear in articular cartilage, a slippery connective tissue that cushions joints. As cartilage thins out, bones in a joint can no longer easily glide past each other. Falls, sports injuries, prolonged immobilization, and other circumstances may damage cartilage in younger people, too. Even very tiny defects in cartilage can enlarge over time, setting the stage for osteoarthritis.
Filling the Holes
Once damaged, cartilage heals very slowly, if at all. Researchers have been exploring various cell-based techniques to promote cartilage regeneration. Transplantation of patients’ own cartilage-producing cells – called chondrocytes – has been tried in the clinic to repair small defects in cartilage. However, the technique has not achieved widespread use because it is difficult to collect sufficient numbers of chondrocytes from patients and grow them in the lab. “The chondrocytes in the arthritic joint are usually [of] inferior quality,” says Jason Burdick, associate professor of bioengineering at the University of Pennsylvania. In addition, cartilage produced by chondrocytes in culture is weaker than the native tissue. Burdick, in collaboration with Robert Mauck, associate professor of bioengineering and orthopaedic surgery at the University of Pennsylvania, and several orthopaedic surgeons at Penn, is working on an alternative approach to engineering cartilage that is more similar to healthy tissue produced inside the body.
A Green Thumb for Growing Cartilage
“One of the unique things about articular cartilage is that it first forms and then matures subsequent to load-bearing use.” Throughout life, mechanical cues regulate development, growth, and maintenance of cartilage. As the body grows and ages, cartilage is restructured. Most other cartilage-engineering approaches replicate only the early stages of development. Burdick’s and Mauck’s goal is to replicate, in the laboratory, what happens during cartilage development from embryo to adulthood.
As quality chondrocytes are a sparse commodity, the researchers turned to mesenchymal stem cells (MSCs) found in the bone marrow. Like plant seedlings that sprout with the right combination of water, light, and temperature, stem cells can be coaxed to transform into specific cell types given the right factors. Depending on the cues they receive, MSCs have the potential to give rise to bone cells, cartilage cells, or fat cells. Ongoing clinical trials are exploring direct injection of MSCs to repair damaged cartilage and heart muscle.
Burdick and Mauck encapsulate MSCs from human bone marrow in three-dimensional scaffolds (hydrogels) made of a substance that is abundant in joints called hyaluronic acid (HA). Along with mechanical loading and relevant chemical cues, HA scaffolds provide an environment that enables MSCs to be converted into chondrocytes and produce cartilage in vitro.
The researchers are still determining what chemical factors are needed, how much to apply, and for how long. In an effort to tailor the mechanical-loading regimens to push MSCs toward producing cartilage, they built bioreactors that provide compressive forces and sliding contact that mimic the natural conditions in a load-bearing joint. “We are trying to optimize the rate by which the tissue forms as well as recreate some of the structure of the native tissue,” indicates Burdick. The HA hydrogel density can be modified to ensure even distribution of cartilage through the gel. In gels that are too dense, uneven distribution results in inferior cartilage quality.
“There is great potential for these cells, but we really need to better understand what they’re going to do once implanted and how to put them in the right environment; that’s where the biomaterials field can play a role,” says Mauck. The implanted engineered constructs should be mechanically stable and integrate well with the surrounding tissue. Because controlling chemical cues in vivo is harder than in vitro, implanted stem cells may start producing bone-like tissue instead of cartilage. Burdick and Mauck recently discovered they could overcome this problem by adding small amounts of chondrocytes to the hydrogel in which MSCs are grown. When chondrocytes are present, MSCs produce a better quality cartilage than when MSCs are used alone. “We are also working on ways to locally deliver various molecules [such as growth factors] using biodegradable particles,” adds Burdick.
In the coming years, Burdick and Mauck plan to test their engineered tissues in animal models of cartilage defects. One of their immediate goals is to repair smaller defects caused by injury to the joint. The technology is readily translatable to humans, as both HA and MSCs are already used in the clinic. “If we can treat focal defects [defects limited to a defined area of the joint], we might be able to decrease the incidence of osteoarthritis five to ten years down the road,” says Mauck. He and Burdick are already thinking about scaling up and modifying their technology so that one day it can be applied to rebuild entire joints.
This work is supported in part by the National Institute of Biomedical Imaging and Bioengineering and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Bian L, Zhai DY, Mauck RL, Burdick JA. Coculture of human mesenchymal stem cells and articular chondrocytes reduces hypertrophy and enhances functional properties of engineered cartilage. Tissue Eng Part A. 2011 Apr;17(7-8):1137-45.