PubMed · 13133788
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B BOGDANIKOWA, T BOGDANIK. 1953-11-09. [Certain so-called flocculation reaction].. https://pubmed.ncbi.nlm.nih.gov/13133788/
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Biomass separation represents a critical bottleneck in Komagataella phaffii-based biopharmaceutical processes, as typically high cell densities of 40 - 50 % create significant operational, technical and economic challenges for harvest operations. Yeast cell aggregation (flocculation) provides a solution to accelerate cell sedimentation by increasing particle size, thus allowing to improve biomass-supernatant separation efficiency during both natural gravity settling and (continuous) centrifugation operations. This study demonstrates successful engineering of K. phaffii strains with an inducible flocculation phenotype using CRISPR/Cas9-based genome editing to integrate the Saccharomyces cerevisiae FLO1 (ScFLO1) gene under control of various regulatory elements, including methanol-inducible and derepressible promoters. Flocculation strength could be enhanced by implementing transcriptional positive feedback circuits based on the methanol-inducible AOX1 promoter. To address methanol-free production requirements, we developed alternative systems to retrofit PAOX1-based ScFLO1 expression and exploited the derepressible PDF promoter, offering broader compatibility with biopharmaceutical manufacturing facilities. Flocculating cells cultivated in a bioreactor demonstrated significantly improved sedimentation behavior, with considerably lower supernatant turbidity after short low-speed centrifugation or gravity sedimentation compared to non-flocculating controls. Crucially, cell flocculation had no negative impact on product amount and quality when expressing a multivalent NANOBODY® VHH molecule with pharmaceutical relevance. Thus, this work establishes the first genetically engineered flocculation system in K. phaffii compatible with recombinant protein production, providing the basis for an innovative approach to streamline harvest operations in biopharmaceutical processes.
A one-dimensional model for the spatio-temporal variation of solids fraction in the blanket considering both the hydrodynamic dispersion and the convection effects was proposed in this study. The model equation was a wave equation whose solution presented shock-wave like characteristic. The model output predicted that the distribution of the solids fraction in the blanket would, firstly, evolve to a uniform distribution at a lower solids fraction. Afterward, the blanket would compact itself to another uniform distribution at a higher solids fraction. Experimental works with synthetic raw water coagulated with PACl suspended in a lab-scale suspended bed confirmed the theoretical predictions. The solids flux plot was constructed with underdosed, optimal and overdosed suspensions. Change in coagulant dose would affect the blanket height and the response time. The solids flux curve was shifted accordingly. The "optimal' operational condition for the upflow suspended bed that produced the lowest effluent turbidity was identified and discussed.
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