Engineering Biomimetic Tissues for Muscle Repair Project Summary/Abstract Skeletal muscle regeneration after severe trauma is often deficient and can lead to loss of function and disability. This has created a significant clinical burden. Although skeletal muscle has significant regenerative capacity, genetic defects, changes in extrinsic signaling, or substantial tissue damage can impair its capacity for self-repair. Large skeletal muscle defects can profoundly impact the quality of life of patients by significantly reducing the functionality of the injured muscles. Currently there is no regenerative standard of care. The long-term goal is to develop an advanced scalable bioengineered tissue that supports muscle growth for validated drug screening models and for therapeutic implantable muscle tissues. The objectives in this application are: to define and incorporate critical physical and biochemical regenerative components within a novel scalable bioengineered muscle tissue; to determine the parameters for controlled and rapid cell loading of a novel bioengineered tissue that can sustain muscle development; and to investigate the physical and biochemical signals that modulate human mesenchymal stem cells (hMSCs) function (in particular, blood vessel formation support) within a novel engineered muscle tissue. The central hypothesis is that an implantable engineered tissue designed with biophysical and biochemical properties that imitate muscle will greatly enhance muscle fiber maturation and blood vessel formation. The specific aims are to: 1) Define the physical and biochemical features of a novel bioengineered biomimetic tissue to develop engineered muscles for drug screening (in vitro) and muscle repair therapies for patients, 2) Investigate an effective method for developing controlled and mature muscle fibers using an engineered biomimetic tissue in vitro, and 3) Investigate the incorporation and function of human Mesenchymal Stem Cells (hMSCs) in an engineered biomimetic muscle tissue to develop vascularized muscle constructs. These results will provide strong proof of principle for further development and future clinical trials of advanced biomimetic muscle tissues, ultimately providing new opportunities for the development of novel therapies for muscle injuries and other related clinical needs (muscular dystrophies, congenital diaphragmatic hernia, iatrogenic skeletal muscle injuries).