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W557:Vandenburgh:HighContentDrugScreeningWithEngineeredMusculoskeletalTissues

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Herman Vandenburgh, Janet Shansky, and Frank Benesch-Lee
Brown University, Dept of Pathology and Myomics, Inc., Providence, RI


Tissue engineering for in vitro drug screening applications based on tissue function is an active area of translational research. Compared to targeted high throughput screening (HTS) methods that rapidly analyze hundreds of thousands of compounds affecting a single biochemical reaction or gene expression, high content screening (HCS) with engineered tissues is more complex and based on the cumulative positive and negative effects of a compound on the multiple pathways altering tissue function. It may therefore be a better predictor of in vivo activity, thus serving as a bridge between HTS and in vivo animal studies. Since high content functional drug screening based on tissue physiology is independent of known mechanisms of action, it may also lead to the identification of new pathways by which tissue function is regulated. In the case of the musculoskeletal system, HCS can be used to identify compounds that improve tissue function, including the mechanical properties of bone, tendon, cartilage, and, for skeletal and cardiac muscle, contractile properties such as rate of contraction/relaxation, force generation, fatigability, and contraction-induced injury. HCS of compound banks with engineered tissues requires generating miniature musculoskeletal ‘organs’ as well as automated functional testing. We have developed an automated technology (MyoForce Analysis System, MFAS™) capable of engineering contractile tissues in 96 micro-well plates with standard liquid handlers and measuring skeletal muscle and cardiac muscle tissue function over days to weeks with customized hardware (MyoForce Analysis Device, MAD™). Each micro-well contains one engineered tissue attached to two flexible micro-posts with known elastic characteristics. To measure muscle function in response to a test compound, an electrical stimulation is applied, causing the muscle to contract and move the flexible posts. Deflection of the micro-posts is recorded by a high speed camera and distance moved converted into micro-Newtons of force with custom algorithms. The system is rapid (20 minutes/plate), sensitive (10 micro-Newtons), cost effective, and reduces the number of animals required for in vivo studies. The newest version of MAD™ (ver. 3.0) not only determines tissue contraction strength and rate of fatigue, but can also apply mechanical loads to the tissue to measure mechanical properties. Using tissues engineered from normal and diseased rodent as well as human muscle, we have screened compound banks, and identified compounds that increase muscle strength, reduce muscle fatigue, and/or attenuate contraction-induced muscle injury. Identification of compounds that improve the repair/regeneration of damaged tissues will have extensive clinical applications for treating numerous musculoskeletal disorders.

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