By Mykl Ambros
The population aged 65 and over in the United States is projected to reach 83.7 million by 2050 and will account for 20% of the total population by 2030.1 In an increasingly aging population, cases of osteoarthritis become more and more common - there are 3 million cases each year in the US alone.2 Osteoarthritis Is caused by the degradation of cartilage in joints, which leads to swelling, stiffness, and chronic pain. Because cartilage is avascular, or doesn’t receive blood from the heart, it is not able to be repaired naturally by the body unlike in skin and bones, where the necessary nutrients for repair to tissue damage are transported through blood vessels. There is currently no known cure for osteoarthritis.
There are several traditional clinical treatments for osteoarthritis, including autologous chondrocyte implantation, microfracture, and allografts. In autologous chondrocyte implantations, cartilage is taken from an area that does not bear a lot of weight, the cells are grown outside of the body for 4-6 weeks, and then implanted into the damaged area. This procedure fails about 15% of the time and requires multiple invasive surgeries to be effective. Microfracture involves removing cartilage from an area of the body and drilling small holes into the exposed bone to cover the it with blood and bone marrow, which will eventually form new cartilage. The unfortunate side to this treatment is that there is a long recovery time and it is ineffective with patients who are overweight, or of advanced age. An allograft is a graft from a donor to the patient. The tissue is not genetically identical, so there is always a chance of rejection by the patient. There is also unfortunately a severely limited supply of viable donor tissue available at times of crisis when patients need it the most.
Fast-relaxing viscoelastic hydrogels provide a possible solution for growing viable cartilage matrix for use in transplants. The relaxation rates are determined by the length of time required for materials of the same stiffness(resistance to non-permanent deformation) to relax to half of an initial stress value, this ranges from 1 minute to 2 hours. A viscoelastic material has both viscous and elastic properties when stress in applied, meaning that a viscoelastic material will dissipate energy over time. Chondrocytes, the only cell found in healthy cartilage, from juvenile cattle were encapsulated in hydrogels of various relaxation rates. After 21 days of culture, actin, type II collagen, and aggrecan (the main proteins of cartilage extracellular matrix) had larger areas of deposition with more interconnectivity in faster relaxing gels than in slower gels.These results can be viewed by immunohistochemical staining and even macroscopically.
Figure 1 Cartilage deposition and macroscopic appearance of hydrogels containing chondrocytes after 21 days of culture. a, Immunohistochemical stains of chondrocytes cultured in 3kPa hydrogels with varying levels of stress relaxation for 21 days. Scale bar, 100μm. b, Increased opacity was observed in hydrogels with faster stress relaxation at day 21, and the size of the constructs were found to be similar. Scale bar, 12mm.3
Faster relaxation rates also directly affect how genes are expressed in chondrocytes. Cells in faster relaxing gels experienced an upregulation of anabolic genes (type II collagen and aggrecan), while slower relaxation upregulates the expression of catabolic genes, (ADAMTS4 and MMP13). Slow relaxation also increases the production of cytokine interleukin-1β (IL-1β) which induces catabolic gene expression and massive chondrocyte apoptosis(cell death) and has been found to be a major driver in the progression of osteoarthritis.
Due to the design and mechanics of cartilage, treatments for degenerative disorders in cartilage associated with aging will be surgical in nature for a long time into the foreseeable future, even with advances in gene editing and therapy. With the potential for lifespans exceeding several hundred years it becomes important to think of long term comfort, and that means that structures that can’t fix themselves must be replaced. A potential new avenue in increased human lifespan is thinking about cartilage engineering.
References:
Ortman, J. M., Velkoff, V. A., & Hogan, H. (2014) An Aging Nation: The Older Population in
the United States. U.S. Census Bureau, P25-1140.
Zhang, Y. and Jordan, J. M. (2010) Epidemiology of Osteoarthritis. Clinics in Geriatric
Medicine, 26, 355-369.
Lee, H., Gu L., Mooney, D. J., Levenston, M. E., & Chaudhuri, O. (2010). Mechanical
confinement regulates cartilage matrix formation by chondrocytes. Nature Materials, 16,1243-1251.