Abstract: We established a human osteochondral-synovium microphysiological system incorporating a single impact mechanical load that emulates initial pathways and biomarker-release of post-traumatic osteoarthritis-like disease; we tested the effects of anti-catabolic dexamethasone and pro-anabolic IGF-1 to ameliorate PTOA-like processes. In addition, we tested the effects of microgravity and radiation ± drugs on this system on the International Space Station. Overall, 88 human distal femurs (Collins Grade 0-2) from 55 donors (M/F age 23-83) were obtained. We quantified release of inflammatory cytokines, cell viability, release of sGAG and ARGS-aggrecan and CTX-II collagen fragments, metabolomics/proteomics assays, and the response to Dex and IGF-1. Two Grade-0 knee-tissues were launched to the ISS on SpaceX-21 for 3-week experiments (M/31, F/47). Analyses showed release of inflammatory cytokines, mainly from synovium, on Earth and in Space, causing increases in release of sGAG and ARGS-aggrecan fragments, the earliest biomarkers of disease by 2-weeks in culture. Metabolites and peptide markers of inflammation were also increased. While Dex+IGF-1 decreased the release of sGAG and ARGS-aggrecan over-all, there was distinct donor-to-donor variability. Metabolomics showed increased oxidative stress and inflammation under spaceflight conditions; Dex+IGF-1 substantially reduced GAG release from one donor system in Space, but the second donor showed less response. Ongoing proteomic analyses focus on extent and kinetics of biomarker release, to aid in the timing and choice of therapeutics. Despite the increasing number and complexity of ongoing clinical trials for OA/PTOA therapeutics, the discovery and choice of drug(s) is only half the battle: the other half is delivery of drug(s) to the intended target(s). Most trials for knee OA/PTOA now involve intra-articularly injected drugs, but there is little or no evidence that injected drugs have reached their target tissues in the dose and duration needed. Does failure of such trials mean that drugs were not efficacious, or that potentially efficacious drugs never reached their intended target at the proper dose/duration due to drug delivery inadequacies?

Biography:  Alan Grodzinsky, ScD, is Professor Emeritus of Biological, Electrical, and Mechanical Engineering in the Departments of Biological Engineering (BE), Electrical Engineering and Computer Science, and Mechanical Engineering at MIT. His research interests center on osteoarthritis and degenerative joint disease; complex microphysiological organ-on-a-chip systems for drug discovery and drug delivery for osteoarthritis; tissue engineering for cartilage repair; cellular mechanotransduction; and molecular, cellular and tissue nanomechanics. He has published over 350 refereed journal articles and reviews in these fields. While his undergraduate and graduate training at MIT was originally in Electrical Engineering and Computer Science, he is a founding faculty member of MIT’s Biological Engineering Department. At MIT, he developed two required graduate courses in BE Department and published a textbook on these subjects (Fields, Forces and Flows in Biological Systems, Garland Science, 2011) focusing on transport and biomechanical properties of connective tissues such as cartilage, skin, tendons and ligaments. He has received numerous awards including the NIH MERIT Award (for research on Cartilage Mechanobiology), the Melville Medal of the ASME, the Kappa Delta Prize of the AAOS, the Borelli Award of the Amer Soc of Biomechanics, the Outstanding Achievement in Mentoring Award of the Orthopaedic Research Society (ORS), the Distinguished Investigator Award of the ORS/AAOS, and the Lifetime Achievement Award of the Osteoarthritis Research Society International (OARSI). 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 is past President of the ORS, the International Cartilage Repair Society (ICRS), and the Society for Physical Regulation in Biology and Medicine. He has consulted for numerous industrial and academic institutions, and USA federal agencies including the NIH, NASA, NSF, FDA, and the Department of Justice.

~ BME Host: Deva Chan ~

Zoom link: https://purdue-edu.zoom.us/j/95124789878?pwd=S0x0VW5Vd3VaMVc1LytlL0NJU1FYUT09

NOTE: Students registered for the seminar are expected to attend in-person.