Bioreactor Core FacilityIntroduction and Specific AimsTissue engineering (TE), i.e., the fabrication of living, 3-dimensional, functional tissue analogs, is a rapidlydeveloping research area that has the potential to revolutionize healthcare. Engineered three-dimensional tissueanalogs are intended to replace tissue; in addition, they can serve as research tools to investigate tissuemorphogenesis and complex cell-cell interactions.The significance of mass-transport limitations grows rapidly with increasing size of a TE construct; in staticculture it can become limiting at construct sizes over a few mm3. At this point, a bioreactor becomes essentialto provide an environment in which nutrient supply and waste removal, but also environmental conditions suchas pH, temperature, or pressure, can be monitored and controlled.Several bioreactor designs have been commercialized; however, these devices remain quite expensiveand complex to operate, and there is little consensus as to what constitutes the best design for a given TE application.Investigators wishing to develop large-scale TE constructs as part of their research program mustcurrently design or purchase their own equipment. Furthermore, TE is now reaching a stage in which the testingof arrays of experimental conditions is becoming critical. Completing such experiments in a timely fashionwill require a large number of reactors. This provides a clear rationale for the establishment of a BioreactorCore Facility, i.e., a laboratory dedicated to providing state-of-the-art technical, instrument, and professionaldevelopment support, and specialized training of faculty, staff and students.All the projects proposed in this Program Project Grant will make use of a bioreactor at one point or another.Case Western Reserve University does not currently have a formal bioreactor core facility. The PI of thiscore facility and his co-workers has developed a modular bioreactor system to address the needs of cartilagetissue engineering. The core reactor design is simple, but highly extensible, to allow for a wide range of treatmentand monitoring modalities. In addition to the projects detailed in this Program Project proposal, this systemhas proven itself in the context of other funded projects. It makes technical, scientific and economic senseto centralize all bioreactor-related steps of these projects, from experimental design, to design and constructionof bioreactor hardware, to the actual bioreactor operation. Further, this will allow the investigators to focusmore of their attention on the basic science questions that are central to their projects.The proposed core facility will emphasize service and core facility research components that are summarizedin the following Specific Aims:
Specific Aim I : to provide a full-service research bioreactor facility to each PPG project, including: State-of-the-art bioreactor culture facilities for Program Project investigators for routine tissue engineering Technical expertise - this core facility would provide trained and skilled personnel for all bioreactor relatedoperations, thus providing the best possible technical expertise. Assistance in experimental design,based on knowledge of the capabilities and limitations of the system, and development of projectspecific,need-driven extensions to the existing system, will be provided.
Specific Aim II : to develop a clinically useful toolset for osteochondral tissue engineering. This researchcomponent will focus on developing elements of a system that will ensure clinical scalability and maximize clinicalutility. These include process monitoring, and data acquisition and control. Specific aspects to be targetedinclude: Bioreactor medium homeostasis, by online monitoring of environmental parameters and feedback controlthrough medium flow rate and/or through the use of buffers. MRI protocol development to monitor implant development non-invasively. Implementation of detailed computer modeling of the bioreactor system as a whole, including hydrodynamicsand gas/nutrient exchange with the construct. Development of disposable versions of the media-wetted bioreactor components for future clinical applications.The core facility will provide all these services and expertise, freeing the Project Pis to focus on experimentaldesign and result interpretation. The core will be complemented by the Cell, Biomechanics, and Morphologycores outlined elsewhere in this proposal, and will benefit by gathering critical information on the requirementsof tissue type investigated, by perfecting computer model templates for different experiment types. These datawill then be available from a single source to aid core users in designing their experiments. We therefore anticipatethat this facility will become an invaluable resource to a significant number of investigators.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZAR1-CHW-J (J1))
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Case Western Reserve University
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