BLRD Research Career Scientist Award Application

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PROJECT SUMMARY / ABSTRACT: Dr. Ngan F. Huang, PhD is a Research Biomedical Engineer whose translational research program focuses on cardiovascular diseases and traumatic muscle injury, both of which are highly relevant in Veteran populations. The overall goal of her research program is to develop novel therapeutic strategies to improve tissue regeneration and functional restoration to cardiovascular and skeletal muscle diseases/injuries experienced by Veterans. These therapeutic strategies are aimed to reduce mortality and improve the quality of life of Veterans. The primary focus area of her laboratory's research program is to study the role of biochemical and biomechanical cues within the extracellular matrix in modulating cell fate and tissue function, in order to translate the basic insights into novel therapies that promote cardiovascular and skeletal muscle regeneration in Veterans. Her active VA BLR&D Merit award focuses on the treatment of traumatic muscle injury using engineered skeletal muscle that better mimics the physiological organization and vascularization of native skeletal muscle. In particular, she employs parallel-aligned nanofibrillar collagen scaffolds to guide the organization and synchronized contractility of newly formed muscle fibers. Additionally, inter-cellular interactions between skeletal muscle progenitor cells and vascular endothelial cells create a vascularized muscle tissue that can undergo anastomosis upon transplantation. Her laboratory reports seminal knowledge in that treatment of pre-endothelialized and parallel-aligned engineered skeletal muscle induces more de novo muscle regeneration, organized myofiber structure, and perfused vasculature, than in engineered muscle lacking pre-endothelization or spatial patterning. Proteomic and transcriptomic analysis reveal new insights into the basic signaling pathways and cytokine profile that mediate this process. In a parallel strategy to augment muscle regeneration, she also developed off-the-shelf scaffolds with controlled release of muscle reparative factors that can be transplanted to the site of VML in conjunction with regenerative rehabilitation. With funding from an active VA RR&D Merit award, she merges rehabilitative exercise with the transplantation of aligned nanofibrillar scaffolds that release pro-myogenic factors to improve vascularization, neuromuscular junction formation, and force generation. These research findings impact the treatment of volumetric muscle loss by synergizing therapeutic cells, instructive biomaterials, and rehabilitation to promote muscle regeneration. Besides skeletal muscle, another research focus area is the treatment of peripheral arterial disease using strategies to induce revascularization. In an active NIH R01 grant, she demonstrates that spatially aligned nanofibrillar collagen scaffolds serve as effective carriers to enhance the pro-survival and pro-angiogenic function of transplanted therapeutic cells, leading to the restoration of blood perfusion in murine models of peripheral arterial disease. The insights gained from the pro-survival effects of aligned nanofibrillar collagen scaffolds have now been patented. In a parallel strategy, she develops protein mimetic hydrogels with tunable stiffness to improve the survival of human induced pluripotent stem cell-derived endothelial cells upon injection mice animals with peripheral arterial disease. She demonstrates that endothelial survival within the ischemic limb of mice with peripheral arterial disease is significantly higher when delivered within the protein hydrogel than in saline. Moreover, the hydrogel promotes induced pluripotent stem cell-derived endothelial cell secretion of angiogenic paracrine factors, which contribute to the formation of more microvasculature. This work is now being further developed in another active NIH R01 grant to study the role of stress relaxation mechanical properties of hydrogels in modulating endothelial cell survival and revascularization. In summary, during the past 10 years at the VA Medical Center, she published 75 peer-reviewed publications and patents. She has a strong commitment to service to the local and national VA, training of VA mentees, and collaborative research with VA and affiliate investigators.