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    Discovery May Lead to Better Treatment for Meniscus Tears, Joint Degeneration

    New research has discovered the underlying biomechanics that may be involved in meniscus fibrocartilage function – as well as dysfunction – and could guide novel treatments for some of the most debilitating and costly orthopedic problems in the US, including meniscus tears and age-related joint degeneration.

    In studies of knee tissue samples from cows and humans, bioengineers funded by the National Institute of Biomedical Imaging and Bioengineering identified small patches of non-fibrous “islands,” known as microdomains, in the knee fibrocartilage that makes up the meniscus. Samples from older animals and humans consistently had larger microdomains.

    The discovery opens the way for a more detailed examination of fibrocartilage microstructure and how changes at the cellular and molecular levels contribute to orthopedic health and disease.

    “This is impressive and important work,” said Rosemarie Hunziker, PhD, Director of the NIBIB Program in Tissue Engineering and Regenerative Medicine, “both in the fundamental discovery and the fact that they rapidly built a model to study it.”

    The research from the University of Delaware and the University of Pennsylvania has been published in the journal Nature Materials.

    Microdomains Grow with Age, Mechanical Stress

    The group examined cow knee tissue samples spanning from fetal development through adulthood. The microdomains, interspersed within the fibrocartilage of the meniscus, were present at the fetal stage in cow samples and grew larger in size, but not number, as the age of the animal increased.

    Studies of human samples revealed the same correlation between advanced age and increased size of microdomains. In addition, human donors with higher body mass index also had increases in the size of the microdomains.

    “Taken together, these observations suggested that increased microdomain size might be an adaptive response to handle increased mechanical load accumulating over time or increased pressure on the meniscus in heavier individuals,” explained Dawn Elliott, PhD, chair of the University of Delaware’s Department of Biomedical Engineering and co-senior author of the study. “

    “An important question we immediately had was whether such an adaptation could be pushed to the point where it could also lead to impaired function of knee fibrocartilage.”

    Investigating Structure and Function at the Micro-level

    Studies of cells in the fiber-rich regions of the tissue and in the microdomains revealed the type of information the team looks for: a critical mechano-responsive difference between the flexible fibers and the inflexible microdomains.

    “There was a distinct change in calcium signaling in response to stretching and increased mechanical loading in cells within the fibrous part of the tissue,” said Robert L. Mauck, PhD, Department of Orthopaedic Surgery and Bioengineering at the University of Pennsylvania and co-senior author of the study.

    “But in cells in the non-fibrous microdomains, calcium levels remained static – these cells were not responsive to stretching or increased mechanical loading.”

    Dr. Mauck explained that calcium movement in and out of the cells in response to tissue stretching is a signal for the cells to activate genes and processes that cause regeneration and remodeling of tissue.

    Conversely, the lack of such a response in the microdomains added evidence to the theory that microdomains could contribute to impaired function, as a knee meniscus with larger microdomains might fall short in its attempt to repair itself in response to stress.

    Building Tissue-engineered Constructs for In-depth Study

    For more detailed studies of the characteristics observed in meniscus samples, the research team engineered knee fibrocartilage in the laboratory.

    They called their laboratory-made knee fibrocartilage heterogeneous tissue engineered constructs or (hetTECs). “Heterogeneous” refers to the fact that the laboratory-made tissue contained the 2 elements observed in the native tissue: the fibrous domains interspersed with islands of the non-fibrous microdomains.

    Dr. Mauck stressed that the different expertise and perspectives of the research team made constructing hetTECs possible.

    “Dr. Elliott’s work in tissue mechanics, essentially drilling down to reveal the micro-level structure of the tissue, provides me with the details I need as a biomaterials and tissue engineering scientist to build an accurate tissue engineered model from the ground up,” he said.

    Extensive testing of the hetTECs demonstrated that they faithfully mimicked the characteristics of the native tissue, including the calcium response to stress in the fibrous areas and the lack of a response by cells in the microdomains. The team is enthusiastic about using the bioengineered hetTECs to answer questions about how the microstructural details relate to the function of knee fibrocartilage.

    Dr. Mauck explained the utility of the hetTECs. “We now have an in vitro platform to study the mechanobiology of knee tissue in a controlled fashion in the lab.

    “For example, we may find that microdomains are necessary for the proper development of fibrocartilage in the embryo, but then become detrimental in aging animals. We are now performing tests that will help us unravel the mechanical details of how the structure relates to function”

    Although they are cautious about blaming microdomains for fibrocartilage degeneration without more extensive testing, the research team acknowledged the powerful potential of their hetTEC constructs for identifying disease processes at the micro-level and then testing potential treatments that reverse or halt the disease process.

    Concluded Dr. Mauck, “Ultimately, we are working to use this type of engineered model to develop new treatments for ailing knees as well as other types of connective tissues.”

    Source

    Han WM, Heo SJ, Driscoll TP, Delucca JF, McLeod CM, Smith LJ, Duncan RL, Mauck RL, Elliott DM. Microstructural heterogeneity directs micromechanics and mechanobiology in native and engineered fibrocartilage. Nat Mater. 2016 Jan 4.