Human Vascular Microphysiological System for in vitro Drug Screening.
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2016-02-18
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In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 μM lovastatin for three days prior to addition of Tumor necrosis factor - α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.
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Fernandez, CE, RW Yen, SM Perez, HW Bedell, TJ Povsic, WM Reichert and GA Truskey (2016). Human Vascular Microphysiological System for in vitro Drug Screening. Sci Rep, 6. p. 21579. 10.1038/srep21579 Retrieved from https://hdl.handle.net/10161/11943.
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Scholars@Duke
Thomas Joseph Povsic
William M. Reichert
Adjunct Professor of Biomedical Sciences, Makerere University, Kampala, Uganda (pending)
Director of the Duke-Makerere BME Partnership
Dr. Reichert's research interests have included biosensors, protein mediated cell adhesion, wound healing, and biocompatibilty. Dr. Reichert was the first member of the engineering faculty to receive the Clemson Award from the Society for Biomaterials (there have since been three others) and elected as a Fellow of the International Union of Societies for Biomaterials Science and Engineering and the American Council on Education. He was also elected as a Fellow of the American Institute of Medical and Biological Engineering and the Biomedical Engineering Society. Dr. Reichert also received recognition for his student mentoring, especially in the area of diversity. The drivers of his career were more than 30 years of uninterrupted NIH support from six different institutes, sustained support from the Medtronic Corporation, and the dedication and brilliance of numerous undergraduate, graduate, postdoc, staff and faculty colleagues. But life moves on.
Dr. Reichert spent the 2014-15 academic year as a Fulbright Scholar (also a school of engineering first) in the fledgling BME program at Makerere University in Kampala, Uganda where he taught six classes in two semesters and conducted a major curriculum revision to increase engineering content. This exhilarating (and exhausting) experience transformed Dr. Reichert’s professional priorities from domestic biomedical research to building BME capacity at Makerere University and in Uganda. With generous funding from the Duke BME Department, Duke University Provost’s Office, the Duke Global Health Institute, the Pratt School of Engineering, and the Duke Africa Initiative, Dr. Reichert launched the Duke-Makerere BME Partnership to accelerate the development of biomedical engineering in Uganda. The Partnership consists of three components.
Undergraduate Education. Currently there are two initiatives. In the fall semester BME525 Biomedical Materials and Artificial Organs is taught to both Duke and Makerere students by broadcasting lectures recorded at Duke to students in Uganda. The students take the same exams, are assigned the same readings, and conduct similar group projects. Real time interaction between the instructor and the Makerere students is accomplished by weekly Skype sessions. The Duke students are encouraged to incorporate some aspect of the Uganda circumstance in their projects. In the spring term Duke offers a class BME590 Transcontinental Design for Uganda where a limited number of Duke and Makerere students participate in mutual design activities to create solutions to healthcare issues in Uganda. This class also includes an option for the Duke students to travel to Uganda during their spring break to meet with and interact with their Makerere design partners. Travel scholarships are provided by the Partnership predicated on financial need.
Master’s Education. Receiving a Master’s degree is a significant step in the professional development of aspiring academics and entrepreneurs In Uganda. Starting in August 2016 the Partnership will be bring two Ugandans with undergraduate BME degrees or a related field to Durham to join Duke BME Master’s Program. A key component of student selection is performance in BME525 and BME590. These students will spend the first two semesters taking BME classes at Duke and also defining their dissertation topics. During the following summer the students will transition back to Makerere for their third and final semester where they complete their dissertation work and possibly take a class. Dr. Reichert will travel to Uganda to join the Makerere faculty members for the dissertation defense, while the other Duke committee members will attend via Skype. All educational and living expenses will be paid by the Partnership except for living expenses while the students are back in Uganda.
Doctoral Training. Unlike the Bachelor’s or Master’s degree, the PhD degree is an immersive research experience. Admission decisions to top science and engineering PhD programs are largely predicated upon evidence of a keen aptitude and substantial commitment to research. Making this determination with non-traditional candidates can be difficult, especially when in-person interviews are not possible. The Duke-Makerere BME Partnership provides an excellent opportunity for the Duke faculty to see the Uganda Master’s students up close and personal. The students that perform at a high level in their Duke classes and on their dissertation projects, and who are committed to pursuing the PhD, will be invited to apply to the Duke BME PhD program as a regular international student.
George A. Truskey
My research interests focus upon the effect of physical forces on the function of vascular cells and skeletal muscle, cell adhesion, and the design of engineered tissues. Current research projects examine the effect of endothelial cell senescence upon permeability to macromolecules and the response to fluid shear stress, the development of microphysiological blood vessels and muscles for evaluation of drug toxicity and the design of engineered endothelialized blood vessels and skeletal muscle bundles.
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