Fetal bovine serum (FBS) is the most widely used growth supplement for cell culture; it cost-effectively supports the survival, growth, and differentiation of many cell lines by providing nutrients, growth signals, and protection from stress. Although serum is an effective growth promoter, it is variable in its composition, activity, and effects on cellular phenotypes. This variability introduces inconsistencies into research using cultured cells. Sometimes it is possible to replicate experimental results only if the same manufacturer's serum is used; sometimes replication is only possible using serum from the same lot. Vendor literature and scientific reviews advise investigators to test lots of serum to identify those that support the desired cellular responses, and then buy a quantity of the best lot for long term use. This practice is widespread but can make replication of results by others difficult.
Serum contains hundreds, perhaps thousands, of constituents. These include macromolecules, small molecules, and trace elements; for any cell line a large and variable subset of these may be active in supporting cell growth. The composition and concentrations of factors in serum vary with the source animals' diets, geographical locations, gestational stages, gender, health, season of harvesting, and histories of exposures to hormones, antibiotics, and environmental chemicals. Harvesting practices, manufacturing processes and additives, and differences in quality control and handling introduce additional variation. Serum is a byproduct of the meat-processing industry; dependence on serum is a barrier to translation of cell-based therapies because of the risk of transmission of viruses, prions, endotoxins, and immunogens.
Serum supplies factors that support cell growth through mechanisms that are not well understood, but includes hormones, enzymes, extracellular vesicles and proteins, extracellular matrix constituents, attachment and spreading factors, vitamins and minerals, trace elements, lipids, protease inhibitors, and other stabilizing and detoxifying factors. Substitute formulations for serum are expensive and time-consuming to develop and are cell-type specific; some cell lines cannot be grown with presently-available serum replacements. Although serum substitutes can support the growth of many cell types in culture, they often do not support robust survival and the same range of responses as does serum. Thus, serum continues to be widely used in many research settings where it is not economically practical to customize substitutes for it.
This Funding Opportunity Announcement (FOA) addresses the needs of developers and users for supporting technologies and products to expedite (a) development of better serum substitutes, (b) identification of serum constituents that are effective in promoting the culture and responses of specific cell lines, and (c) troubleshooting of experimental variation stemming from variability in serum. This FOA will support STTR projects to develop reliable and cost-effective tools; projects may develop new technologies or improve upon existing technologies. Topics include, but are not limited to:
- Synthetic serum replacements, both general purpose and specialized for particular cell types. Development of minimal base formulations for customization by users into serum substitutes for specific cell lines.
- General purpose analytical tools to detect constituents in serum. Tools for rapid evaluation of variation in serum composition, and for comparison of serum batches.
- Specialized methods, tools and products for identification and evaluation of factors and activities in serum affecting adherence, survival and phenotypes of particular cell types.
- Development of bioactive products for inclusion in serum replacements or to supplement reduced media, such as components that would assist the adherence of cells and promote correct morphology.
- Affordable methods for production of serum components such as growth factors.
- Toolkits to assist users to develop serum replacements.
- Methods, tools, and products for detecting and clearing biological and chemical contaminants, such as viruses, prions, endotoxins, immunogens, etc.
See Section VIII. Other Information for award authorities and regulations.