BIOMATERIALS FOR CARDIOVASCULAR TISSUE ENGINEERING

University Of Delaware, Newark DE

Investigators

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The engineering of cardiovascular (CV) grafts that mimic the properties of native tissue remains a formidable research and clinical challenge and a principal area for translational research emphasis. In particular, controlling the organization of cells in engineered tissues is a critical issue, and there is a important and well-recognized need to identify physical and molecular pathways that can be manipulated to direct the formation of desirable constructs. Unfortunately, little is known about (i) the types of physical substrates that might be most effective in guiding multi-cellular assembly, (ii) the cellular mechanisms that drive the formation of integrated structures ex vivo, and (iii) the effects of organizational strategies on the component cells of engineered tissues. With this application, we seek initial funds for a new interdisciplinary research program to address these areas within the context of developing critically-needed implants to treat congenital and acquired CV disease. Mammalian CV systems are essentially closed, fluid-filled networks of conduits that contain varying degrees of muscle to control luminal volume and restrict or generate flow. Implantable biosynthetic conduits that reproduce essential CV functions would be valuable for the treatment of adult disease but are also uniquely suited for the repair of pediatric defects. Indeed, CV tissue engineering will offer opportunities for the growth and remodeling of implants while minimizing thrombogenesis and intimal hyperplasia and providing for appropriate physiologic responsiveness and graft self-renewal over the lifetime of the implant recipient. Our long-term goal is the development of composite ves-sels (see Figure 1) with bio-synthetic components that act initially as scaffolds to provide mechanical support while recruiting the appropriate cellular/biological components but that later degrade leaving a completely biologic vessel. The development of such implants will require advances in multiple areas including, 3D fabrication technologies, molecular and physical mechanisms to control cell distribution and function, and evaluating interactions between scaffold materials, cells, and the host physiology. Once fully developed, envisioned applications would involve (i) production of synthetic composite tubes comprising nonoriented and oriented nanofibrous scaffolding, (ii) seeding with autologous cells to populate the layers and establish a biosynthetic device that responds to the in vivo mechanical and humoral environment, and (iii) implantation into a host where conversion to a completely biological conduit would proceed by interaction with the host physiology. Thus, there are substantial areas of research needed in the field and clear opportunities for interdisciplinary research programs. Accordingly, we have assembled a research team composed of investigators with expertise in polymer and biopolymer design, polymer characterization, CV cell biology and physiology, human CV pathophysiology, and system biology so that the properties of engineered CV grafts can ulti-mately be engineered from the molecular through the macroscopic, optimized, tested and prepared for eventual transfer into the clinical setting. The proposed research is interdisciplinary and cross institutional involving investigators from the Alfred I duPont Hospital for Children, the DuPont Expe-rimental Station, and the University of Delaware. Together, the team will develop an interdisciplinary research program in CV engineering using funds from INBRE to seed key areas of research and sponsor two graduate students, who will be under the direct supervision of Drs. Akins and Rabolt. Undergraduates will be encouraged to participate in the research program by working in the lab for course credit or in preparation for senior honors theses in their home department, and a course focusing on cardiovascular dynamics and the associated engineering challenges will be developed for advanced undergraduates and graduate students. The investigators will continue to submit conventional and MPI-based R01 applications to further the development of the scientific goals of the program and to continue the development of graduate and undergraduate training initiatives in CV tissue engineering beyond the time-frame of the INBRE mechanism. The present application centers on two focused aims that address areas critical to the development of the interdisciplinary program. Both aims center on the muscular component (i.e. medial layer) of biosynthetic conduits (see Figure 1). The first aim investigates the preparation of a complex composite conduit evaluated with a simple cell system [unreadable]human smooth muscle cell line, and the second aim investigates the effects of a relatively simple biomaterial on the complex cell:cell interactions found in primary cardiac cells. This design takes full advantage of the expertise of the research team, leverages available INBRE Core Resources, and fits within the budgetary requirements of the INBRE me-chanism.