Journal
OSTEOARTHRITIS AND CARTILAGE
Volume 22, Issue 9, Pages 1282-1290Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.joca.2014.06.032
Keywords
Injurious compression; Impact loading; High-throughput screening; Tissue engineering; Cartilage tissue analog (CTA)
Categories
Funding
- AO Foundation Exploratory Research Board Acute Cartilage Injury Consortium
- Department of Veterans Affairs
- National Science Foundation
- Penn Center for Musculoskeletal Disorders
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Objective: A number of in vitro models of post-traumatic osteoarthritis (PTOA) have been developed to study the effect of mechanical overload on the processes that regulate cartilage degeneration. While such frameworks are critical for the identification therapeutic targets, existing technologies are limited in their throughput capacity. Here, we validate a test platform for high-throughput mechanical injury incorporating engineered cartilage. Method: We utilized a high-throughput mechanical testing platform to apply injurious compression to engineered cartilage and determined their strain and strain rate dependent responses to injury. Next, we validated this response by applying the same injury conditions to cartilage explants. Finally, we conducted a pilot screen of putative PTOA therapeutic compounds. Results: Engineered cartilage response to injury was strain dependent, with a 2-fold increase in glycosaminoglycan (GAG) loss at 75% compared to 50% strain. Extensive cell death was observed adjacent to fissures, with membrane rupture corroborated by marked increases in lactate dehydrogenase (LDH) release. Testing of established PTOA therapeutics showed that pan-caspase inhibitor [Z-VAD-FMK (ZVF)] was effective at reducing cell death, while the amphiphilic polymer [Poloxamer 188 (P188)] and the free-radical scavenger [N-Acetyl-L-cysteine (NAC)] reduced GAG loss as compared to injury alone. Conclusions: The injury response in this engineered cartilage model replicated key features of the response of cartilage explants, validating this system for application of physiologically relevant injurious compression. This study establishes a novel tool for the discovery of mechanisms governing cartilage injury, as well as a screening platform for the identification of new molecules for the treatment of PTOA. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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