A genetically engineered bacterium now churns out seven times longer chains of hyaluronic acid—the natural lubricant found in human joints and skin—at up to 50 times the usual yield in a lab flask. Current manufacturing relies on wild bacterial strains that produce short polymer chains, topping out at around 4.5 million daltons. For medical uses that demand longer chains—such as injecting cushioning fluid into arthritic knees—manufacturers must chemically stitch shorter chains together. That extra step adds cost and can trigger adverse reactions in patients. The researchers have already built bacterial strains that produce hyaluronic acid chains up to 7 million daltons at lab scale, and a 5-litre fermenter test suggests the process can be scaled up. If the team succeeds in developing industrially robust strains and a scalable fermentation process, the UK could capture a significant share of the multi-billion-pound hyaluronic acid market. The result would be cheaper, safer biomedical products—from dermal fillers to eye-surgery replacements—without the need for chemical cross-linking. This is applied engineering biology aimed directly at commercial spin-out, not fundamental science.
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Hyaluronic acid (HA) is a naturally occurring polymer which is important for human health and development. HA is found in the synovial fluid of joints, the skin, and the vitreous humour of the eye. The length of the polymer and the ability to absorb water make this compound an excellent biological lubricant. HA has numerous commercial applications, for example, in cosmetics as a hydrating agent and dermal filler, and in ophthalmic surgery to replace vitreous material lost during cataract lens replacement. The mechanical properties of HA are also used to supplement loss of synovial fluid in osteoarthritic joints. These varied uses make HA a high-value biomedical product with a multi-billion pound market value. Eukaryotic HA can reach a molecular weight (MW) of up to 14 MDa. The MW of HA is key to its mode of action wherein the higher the MW, the greater its efficacy in relevant biomedical procedures e.g. cushioning effect following injection into arthritic joints. Current manufacturing processes use fermentation of wild type bacterial species that naturally synthesise HA. This approach limits the MW of HA that can be produced, with the current market dominated by HA with a MW of approximately 3-4.5 MDa. Some specialised biomedical applications require HA with a much higher MW, this is achieved by chemically cross-linking smaller polymer units to generate a higher MW product, which adds costly chemical processes and clean-up procedures into the manufacturing process. Addition of cross-linking chemicals can also cause adverse reactions in patients. We have used an engineering biology approach to build a platform technology which allows production of HA up to 7 MDa and a 33-50-fold increase in yield within the laboratory environment (0.5L scale). We have recently completed a small scale up assessment using a 5L fermenter which indicates the process is scalable. Together, our technological advances provide a potential advantage in a global market which could place the UK at the forefront of HA manufacturing. This will provide better biomedical products at lower cost and with greater patient safety. The goal of this project is to de-risk our platform technology for commercial deployment through two specific goals: 1) Further develop our proprietary bacterial strains to establish industrially robust, high performing strains with enhanced HA production, and 2) Develop a fermentation scale-up process to validate production as the next step in creation of a ‘spin-out’ company.
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