# Bioreactors: Applications and Innovations for a Sustainable and Healthy Future--A Critical Review
## 6 Recent Advances in Bioreactor Applications
### Cell Culture and Tissue Engineering
Recent publications suggest a likely direction for widening the applicability of this in supporting regenerative medicine and strategies for continuous bioprocessing and developing systems for the metabolic responses of non-natively stress-induced cells maintained in vitro [121,122]. [PERSON] et al. [102] investigated scaling mammalian cell culture processes over different stirred and aerated bioreactors ranging from 15 mL to 15,000 L using computational and experimental methods. Key parameters (maximum hydrodynamic stress, mixing time, and oxygen mass transfer coefficients) were determined experimentally for all scales. Computational fluid dynamics simulations integrating time-averaged equations of motion for fluid flow and considering bubble size population balance equations pointed to local and average hydrodynamic stresses and mass transfer coefficients. This integrated approach supports Quality-by-Design strategies, facilitating the transfer of mammalian cell cultures across reactors of different geometries. For controlling cell behavior, the integration of nano-vibrational stimulation mechanisms (initially designed via computer simulations and verified using laser interferometry) offers an interesting alternative [123]. It is important to point out that gamma-sterilized single-use plastic equipment plays a crucial role in reducing manufacturing costs, increasing plant flexibility, and shortening turnaround times while ensuring a safe and regulatory-compliant product. These characteristics support the needs of the biopharmaceutical industry, and the issue of leachables has been addressed for decades [124]. For example, 3,5-Dinitro-bisphenol A, found in extracts from polycarbonate flasks, can arrest the cell cycle in CHO-S cells, while bis(2,4-di-tert-butylphenyl) phosphate (bDtBPP), a prominent leachable, has growth-inhibiting effects on cell cultures [125]. Two of the most common leachables are plasticizers and antioxidants, which are typically used in the production of polymeric materials. These substances can be released during the sterilization process, through exposure to solvents, mechanical stress, or even under normal culture conditions, posing risks to cell viability and bioproduction consistency [126]. Therefore, it is essential to monitor the levels of leachables and their effects, especially in single-use devices, which are often used with plastic bags. Regarding plant cells, the distinct types of bioreactors currently used for quality biomolecule production are discussed, with a focus on some species used to obtain important metabolites, by [127], with an insight into the type of bioreactor and production protocols. To support bioreactor design, computational simulations are a powerful tool to avoid trial-and-error approaches. The discussion includes general and stimulus-specific requirements (e.g., perfusion, mechanical, and electrical) that must be considered during the design phase based on the tissue target. Computational models support designing bioreactors based on the provided stimulus, with a special focus on additive manufacturing techniques [128; 129]. The ultimate trend in tissue engineering is cultured meat. Reviewing the literature highlights several studies indicating that some bioreactor systems are best suited for producing a particular sort of meat product in vitro and might not work well for producing meat in other forms or sizes. Therefore, there is still progress to be made in this area [130; 131].