The Sources of Hyaluronic Acid: From Animals to Microorganisms

Hyaluronic acid is a naturally and ubiquitously occurring substance found in various organs and tissues of mammals, including for example the skin, skeletal muscles, eyes, synovial fluid between joints, and the umbilical cord. Historically, the industrial production of hyaluronic acid has relied on animal tissues such as rooster combs due to their high concentration of this valuable compound. However, the extraction process from animal sources can be complex and costly, and it also raises ethical and contamination concerns.

Microbial Hyaluronic Acid Production

Microbial hyaluronic acid production has emerged as a promising alternative to animal-based sources¹. Extensive research in bacterial fermentation has shown that bacteria can produce hyaluronic acid identical to that found in animal tissues. Thus, the risk of triggering immune responses is significantly reduced as compared to animal-sourced hyaluronic acid, making it suitable for medical-grade products and cosmetic applications. Moreover, microbial production methods avoid the ethical issues associated with animal-derived hyaluronic acid.

Several bacterial species, including genetically engineered strains, have been identified as efficient producers of hyaluronic acid². The ability to manipulate these microorganisms at the genetic level allows for optimized production processes, leading to higher yields and purer products. In addition, the biotechnological production of hyaluronic acid with bacterial strains does not provide any potential additional glycosaminoglycans of the extracellular matrix, as can be the case with the isolation of the biopolymer from animal tissue, as it forms complexes with other proteoglycans.

Current Challenges

Despite the many advantages of microbial hyaluronic acid production over using animals for sourcing and manufacturing hyaluronic acid products, there are some limitations. One major challenge is the purity of the hyaluronic acid produced. The production process, i.e. the bacterial fermentation, can sometimes result in impurities that need to be meticulously removed, adding to the complexity and cost of the procedure. Furthermore, the yield of hyaluronic acid from bacterial fermentation can vary, impacting the scalability of this method for industrial applications.

Enzyme-Based Synthesis: A New Frontier

One innovative approach to optimize hyaluronic production is based on the use of enzymes from Class I and Class II hyaluronic acid synthases in cell-free systems, i.e. without the use of animal tissues or microbes³. This enzyme-based approach has the potential to overcome issues related to purity and contamination, offering a more controlled and efficient production process.

The enzymes involved in the natural in vivo hyaluronic acid biosynthesis are particularly those from the Class I and Class II hyaluronic acid synthases family⁴. Class I synthases are typically found in eukaryotic organisms, while Class II synthases are more common in prokaryotic organisms like bacteria. Both classes have distinct mechanisms and properties that influence their effectiveness in hyaluronic acid production.

Understanding the functionalities of these enzymes is key to optimizing the enzyme-based synthesis process. For example, genetic modifications and the use of co-factors aim to enhance the activity and stability of these enzymes. By fine-tuning such parameters, the goal is to significantly improve the yield and quality of hyaluronic acid produced through enzyme-based methods.

Although promising, this innovative method is still in the early stages of development making it not yet viable for industrial-scale production. Current strategies aim to optimize these cell-free systems to enhance their efficiency and output to make enzyme-based hyaluronic acid synthesis a feasible alternative in the near future.

1. Serra, M., Casas, A., Toubarro, D., Barros, A. N. & Teixeira, J. A. Microbial Hyaluronic Acid Production: A Review. Molecules 28, 2084 (2023).
2. Ciriminna, R., Scurria, A. & Pagliaro, M. Microbial production of hyaluronic acid: the case of an emergent technology in the bioeconomy. Biofuels Bioprod. Biorefining 15, 1604–1610 (2021).
3. Jing, W. & DeAngelis, P. L. Synchronized Chemoenzymatic Synthesis of Monodisperse Hyaluronan Polymers. J. Biol. Chem. 279, 42345–42349 (2004).
4. DeAngelis, P. L. & Zimmer, J. Hyaluronan synthases; mechanisms, myths, & mysteries of three types of unique bifunctional glycosyltransferases. Glycobiology 33, 1117–1127 (2023).