Novel Manufacturing Processes for Tissue Engineered Vascular Grafts

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DESCRIPTION (provided by applicant): Engineered tissues are revolutionizing disease therapy in many areas of medicine. It is estimated that the total market size for all types of tissue engineered therapies was $1.5 billion in 2008. But for many types of engineered tissues, including engineered cartilage, bladders, and blood vessels, clinical manufacturing production adheres closely to the original benchtop processes that were used during the early discovery of the technology. Across the industry, limitations in scale up and automated control of engineered tissue production lead to high costs of goods and potential product variability that may impair clinical outcomes. Hence, innovative methods for controllable, scale-able, and affordable tissue production are urgently needed. The ultimate objective of this proposal is the development of technologies that will improve the manufacturing of engineered human tissues. The Humacyte vascular graft is produced by culturing allogenic human vascular smooth muscle cells on a tubular, biodegradable polymer matrix inside of a flow bioreactor. After culture, the grafts are subjected to a quantitative decellularization procedure, which removes the antigenic cellular components while retaining excellent mechanical characteristics. These grafts can be implanted in any human recipient because, lacking cellular material, they are not immunogenic. The graft is easy to store and has a long shelf life. This "off-the- shelf" engineered arterial graft has many functional advantages over the clinical "gold standard", PTFE grafts, including an expected resistance to infection and a very low incidence of intimal hyperplasia. In Humacyte's current manufacturing process, culture inputs are documented, but consumption of media components, pH, and other parameters are not monitored. Further, no systems are in place for control of such manufacturing parameters. Lastly, the current bioreactor is not amenable to scaled production for clinical production, since it contains multiple components that must be assembled by hand, contains many connections that are susceptible to microbial contamination, and is not compliant with FDA guidelines for GMP manufacturing. In this proposal, we plan to overcome these limitations by developing a novel, scale-able bioreactor prototype that is fitted with complete process monitoring for arterial graft manufacture. Humacyte's grafts, being made from banked allogenic cells, are much more amenable to scaled production and large batch sizes than products that are made from autologous cells. In this effort, Humacyte will collaborate with Xcellerex, a company that has created state-of-the-art manufacturing systems for cell culture and for biomolecule production. Xcellerex has developed single-use, flexible bioreactor systems that are coupled to automated sensing and control systems to provide continuous monitoring of bioreactor cultures. By re-designing the bioreactor into a single-use and single- component bag system, we will be able to dramatically decrease labor costs and contamination risk that are associated with bioreactor assembly and maintenance. PUBLIC HEALTH RELEVANCE: The proposed work will develop a novel type of flexible, single-use, disposable bioreactor for culture of tissue engineered dialysis grafts. Difficulties in manufacture and upscaling of tissue engineered products have hampered translation of many new therapies to the clinic. In this proposal, we will develop a disposable, prototype bioreactor that will allow ongoing, automated monitoring of bioreactor culture conditions and efficient upscaling of manufacturing methods. Work in this application will pave the way for growing novel dialysis grafts for patients with end-stage renal failure, and will also help the field of regenerative medicine as a whole, by developing a novel concept in scaled tissue culture.