Aggrecan Nanomechanics: Relevance to Cartilage Function, Drug Discovery, and Drug Delivery

Friday, October 28, 2016 -
2:00pm to 3:00pm
FUNG Auditorium, Powell-Focht Bioengineering Hall
Alan J. Grodzinsky, Sc.D.

Professor of Biological, Electrical and Mechanical Engineering

Massachusetts Institute of Technology

Aggrecan Nanomechanics: Relevance to Cartilage Function, Drug Discovery, and Drug Delivery

In studies of cartilage degradation and repair, it is important to assess the mechanical function of newly synthesized tissue and constituent matrix molecules at the nano-molecular scale. We recently developed an AFM-based wide-bandwidth rheology system to measure the dynamic nanomechanical behavior of normal and degraded cartilage. A similar approach has enabled assessment of the poroelastic behavior of aggrecan molecules end-grafted to substrates for AFM-based nanoindentation in the frequency range 1Hz to 10 kHz. (The higher frequencies are particularly relevant to impact injury to cartilage and its matrix, associated with traumatic damage to the joint). Traumatic joint injury can initiate early cartilage degeneration in the presence of elevated levels of inflammatory cytokines, leading to post-traumatic osteoarthritis (PTOA). However, there are currently no disease modifying drugs for osteoarthritis, and a major challenge is the ability to achieve sustained levels of potential therapeutics inside a target tissue, with no off-target side effects, after intra-articular delivery. We use in vitro organ culture models to study the beneficial effects of dynamic strain and combination therapeutics (e.g., glucocorticoids, growth factors) to inhibit matrix degradation and cell apoptosis in cartilage explants challenged with cytokines and impact injury. Parallel in vitro and animal studies are aimed at approaches to targeted delivery of drugs inside cartilage. In particular, electrostatic interactions with aggrecan inside cartilage matrix enable charge based intra-cartilage delivery of single dose drugs using cationic Avidin nano-carriers. Studies show that Avidin-based delivery to chondrocytes in cartilage can suppress cytokine-induced catabolism long term in a cartilage explant model. 

Alan Grodzinsky is the Director of MIT's Center for Biomedical Engineering and is Professor of Biological, Electrical and Mechanical Engineering in the MIT Departments of Biological Engineering, Electrical Engineering and Computer Science and Mechanical Engineering. His research interests include the degeneration and repair of cartilage in injured and arthritic joints, cellular mechanobiology, molecular nano-mechanics, cartilage tissue engineering, and transport in tissues relevant to drug delivery and cartilage repair. He has published over 300 refereed journal articles and reviews in these fields of research. He is past President of the Orthopaedic Research Society (ORS) and the International Cartilage Repair Society (ICRS). He is on the Editorial Boards of Osteoarthritis & Cartilage and Biophysical Journal, and has been on the boards of Journal of Orthopaedic Research, Arthritis and Rheumatism, Archives Biochemistry Biophysics, and Polymer Networks and Gels. Dr. Grodzinsky is a recipient of the NIH MERIT Award, the Melville Medal of the ASME, the Borelli Award of the ASB and the Kappa Delta Award of the American Academy of Orthopaedic Surgeons. He was elected Founding Fellow of the American Institute of Medical and Biological Engineering, and is past Chair of the Gordon Research Conference on Musculoskeletal Biology and Bioengineering. He received the Honorary Doctorate from the University of Montreal and was recently nominated to be Honorary Life Fellow of International Orthopaedic Research by the International Orthopaedic Research Societies (ICORS).  He co-developed two of the required core graduate courses in the Biological Engineering Ph.D. Program at MIT, and published a textbook related to these subjects on “Fields, Forces and Flows in Biological Systems” (Garland Science, 2011). He was Chair of the BE Graduate Program for 10 years, and was co-developer of MIT’s first interdepartmental minor, that in Biomedical Engineering.