# Bioreactors: Applications and Innovations for a Sustainable and Healthy Future--A Critical Review
## 6 Recent Advances in Bioreactor Applications
### Cell Culture and Tissue Engineering  
Tissue engineering integrates biology, engineering, and material science to innovate in repairing and enhancing damaged tissues, showing potential to transform regenerative medicine by addressing challenging diseases and injuries [91; 92]. bioreactors are crucial for advancing tissue engineering by enabling scalability, making the technology more accessible and cost-effective, and providing controlled environments for the in vitro growth of functional tissues [93]. However, mammalian cells must maintain strict culture conditions, including temperature (approximately 37 \({}^{\circ}\)C), pH (7.2-7.4), and oxygen levels; environmental control is critical for maintaining cell viability and functionality, so smooth circulation and homogeneity of nutrients and metabolites must be ensured to avoid damage to shear-sensitive cells, which lack cell walls and are voluminous [94]. The customization of bioreactors for different tissue types is a promising area. Each tissue type requires specific growth conditions, and the ability to adjust bioreactors to meet these needs represents a significant advancement. Multidisciplinary collaborations among engineers, biologists, medical professionals, and material scientists are driving innovationsand fostering the development of more sophisticated and effective bioreactors [95]. For this purpose, in silico studies have brought advancements in optimizing the mechanisms incorporated into bioreactor equipment [96; 97]. Prospective manufacturers interested in exploiting animal cells face challenges in selecting from numerous cell preparation methods and reactor designs: microcarriers, microcapsules, suspended cells, the Mass Culturing Technique (MCT), hollow fibers, spiral tubes, compartmented ceramic cylinders, air-lift reactors, gently stirred tanks, disposable rocking (wave) crossflow reactors, compartmented plates, and stacked plate units [94]. Eukaryotic bioreactors are like miniaturized laboratories, providing a controlled and optimized environment for the cultivation of eukaryotic cells, such as animal and plant cells. They are essential tools for a variety of fields, from scientific research to the industrial production of medicines and bioproducts. However, the handling of these bioreactors presents several challenges that can impact their efficiency and effectiveness [98; 99; 100]. Among these challenges we can mention the following:  
* Scale-Up: Scaling up from laboratory to industrial scale can be complex. Maintaining optimal conditions such as aeration, agitation, and nutrient supply is crucial but challenging [101; 102]. * Shear Stress: Eukaryotic cells are often more sensitive to shear stress caused by agitation and aeration, which can lead to cell damage or death, affecting overall productivity [97; 103]. * Contamination: Eukaryotic cultures are more prone to contamination by bacteria, fungi, or viruses, which can compromise the entire bioprocess [104; 105]. * Nutrient Supply and Waste Removal: Ensuring a consistent supply of nutrients and efficient removal of waste products is critical. Imbalances can lead to reduced cell growth and productivity [106]. * Oxygen Transfer: Eukaryotic cells, especially mammalian cells, have high oxygen demands. Efficient oxygen transfer is essential but can be difficult to achieve in large-scale bioreactors [96; 107]. * Cost: The cost of maintaining eukaryotic bioreactors, including media, supplements, and equipment, can be significantly higher compared to prokaryotic systems [108]. These challenges require careful consideration and innovative solutions to optimize bioreactor performance for eukaryotic cell cultures. Initially, bioreactors for eukaryotic cells were used to produce therapeutic proteins, monoclonal antibodies, and cell biology studies. However, with the advent of tissue engineering, the challenges have intensified, necessitating the cultivation of cells in three dimensions for small to medium-sized tissue constructs [109; 110] and even entire organs [111].