Modeling the Effect of TNF-α upon Drug-Induced Toxicity in Human, Tissue-Engineered Myobundles.

TitleModeling the Effect of TNF-α upon Drug-Induced Toxicity in Human, Tissue-Engineered Myobundles.
Publication TypeJournal Article
Year of Publication2019
AuthorsBNJ Davis, JW Santoso, MJ Walker, CE Oliver, MM Cunningham, CA Boehm, D Dawes, SL Lasater, K Huffman, WE Kraus, and GA Truskey
JournalAnnals of Biomedical Engineering
Date Published04/2019
Abstract

A number of significant muscle diseases, such as cachexia, sarcopenia, systemic chronic inflammation, along with inflammatory myopathies share TNF-α-dominated inflammation in their pathogenesis. In addition, inflammatory episodes may increase susceptibility to drug toxicity. To assess the effect of TNF-α-induced inflammation on drug responses, we engineered 3D, human skeletal myobundles, chronically exposed them to TNF-α during maturation, and measured the combined response of TNF-α and the chemotherapeutic doxorubicin on muscle function. First, the myobundle inflammatory environment was characterized by assessing the effects of TNF-α on 2D human skeletal muscle cultures and 3D human myobundles. High doses of TNF-α inhibited maturation in human 2D cultures and maturation and function in 3D myobundles. Then, a tetanus force dose-response curve was constructed to characterize doxorubicin's effects on function alone. The combination of TNF-α and 10 nM doxorubicin exhibited a synergistic effect on both twitch and tetanus force production. Overall, the results demonstrated that inflammation of a 3D, human skeletal muscle inflammatory system alters the response to doxorubicin.

DOI10.1007/s10439-019-02263-8
Short TitleAnnals of Biomedical Engineering