Engineering matrix-derived microcarriers as tissue-specific cell culture and delivery platforms

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Cellular behaviour is highly influenced by the microenvironment, both in culture and in the body. Within mammalian tissues, cells reside in a complex three-dimensional (3-D) system that has tissue-specific composition and architecture. More specifically, cell responses are mediated through dynamic interactions with the extracellular matrix (ECM), which is a complex network of proteins and carbohydrates that regulates the structure and function of tissues. Despite the known importance of the microenvironment, the vast majority of cell culture studies to date have relied on simplified model systems that involve growth on rigid two-dimensional plastic substrates under static conditions. Culturing cells within these systems can cause alterations in cellular responses that may impact the reliability of these models for understanding how cells behave within living organisms, which is needed for applications including stem cell research, disease modeling, and drug development. Recognizing the significant need for improved cell culture models, the focus of Dr. Flynn's NSERC Discovery Grant program is on the development of a range of ECM-derived scaffolds for use in mammalian cell culture and tissue engineering. Over the next 5 years, this grant will support the training of 5 graduate and 5 undergraduate students who will develop tissue-specific microcarriers derived from proteins sourced from discarded fat, cartilage, and bone for use as cell culture and delivery platforms. These spherical microcarriers (less than 0.5 mm in diameter) will be designed to support cell attachment and proliferation. To further tune the cellular microenvironment, the cell-seeded microcarriers will be cultured within bioreactor systems that will allow careful control and monitoring of the cell density, stirring rate, and oxygen tension, which are important regulators of cellular behaviour. The team will investigate the application of this new technology as: i) tissue-specific dynamic culture substrates for directing the lineage-specific differentiation of adult stem cells isolated from fat or bone marrow for future cell therapy applications, ii) platforms for studying mature cartilage cells in culture, and iii) building blocks for constructing 3-D “mini-tissues” for use as model systems or in tissue engineering. Overall, this research will develop a promising and flexible technology platform that may enable biological researchers to more accurately model cell responses within the body. Further, this program will provide invaluable training opportunities for the next generation of researchers in the emerging multidisciplinary fields of stem cells, biomaterials, and tissue engineering. The long-term goals are to translate this technology to be of economic benefit to Canada and to apply these improved culture models to develop more effective therapies to improve the quality of life of Canadians.