Soheil Kianirad,1,*Zahra-Beagom Mokhtari-Hosseini,2Ashrafalsadat Hatamian-Zarmi,3Mohammad Naji,4Elham Ansari,5Zahra Kazemizadeh,6
1. Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran 2. Department of Chemical Engineering, Faculty of Petroleum & Petrochemical Engineering, Hakim Sabzevari University 3. Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran 4. Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences 5. Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran 6. Department of Chemical Engineering, Faculty of Petroleum & Petrochemical Engineering, Hakim Sabzevari University
Introduction: Tissue engineering is the regeneration or reconstruction of living and functional tissue to treat injuries or diseases. Its three key components are cells, scaffold, and provision of a culture medium that mimics the physiological conditions to stimulate and cultivate cells. In body, there are mechanical and biochemical interactions between cells and their extracellular matrices. In earlier studies of tissue engineering, static culture medium was used. Disadvantages and limitations of this classical method include inhomogeneity of nutrient concentration, accumulation of waste materials, lack of mechanical signals in culture medium and inefficiency in the production of three-dimensional tissues. A bioreactor was used to overcome the limitations and create a dynamic culture medium for cells. Bioreactors are commonly used in tissue engineering and include a variety of types such as perfusion, Spinner flask, rotating wall vessel, hollow fiber membrane, mechanical stimulation and biaxial rotating. One of the most similar bioreactors to the natural conditions of the body are perfusion bioreactors. In the past, the transfer of cell suspension to scaffold pores was done manually, relying on the force of gravity. In 3D scaffolds, the force of gravity alone cannot transfer cells and nutrients into the pores of the scaffold. The best available approach that results in uniform and effective cell seeding in scaffolds is the perfusion method.
Methods: In this review, information collected from articles related to perfusion bioreactors and their simulation and modeling were used to provide a summary of their recent advances, applications, Advantages, and limitations.
Results: Bioreactors in tissue engineering mimic the physiological conditions, producing functional tissue to repair or replace damaged tissue. Perfusion bioreactors are one of the most widely used bioreactors in tissue engineering, which by injecting the culture medium into the culture chamber, provide conditions similar to the blood supply to cells through the arteries. In these bioreactors, the continuous flow of culture medium passes through the surface of cells in a pulsating or non-pulsating manner, and the process of absorbing nutrients and removing waste products from cells are similar to the body.
Perfusion bioreactors have been used in tissue engineering for various applications. For example, Perfusion bioreactors were used in liver tissue engineering for cell viability enhancement, in adipose tissue engineering by creating hypoxic conditions to increase cell proliferation, and in cartilage tissue engineering by changing the relative pressure of oxygen to produce the cartilage tissue. They were used in bone tissue engineering to increase nitric acid production and bone differentiation of cells by increasing shear stress, and in another study, by applying perfusion and rotational mechanical forces, cell proliferation and increasing in alkaline phosphate enzyme expression were achieved. This bioreactor was utilized in tracheal tissue engineering to investigate the effect of fluid transfer mechanism on wall shear stress and cell seeding. Moreover, with the help of perfusion bioreactor, mechanical stimulation was applied to study cell proliferation in urethral tissue engineering. Also, it was used in ureter tissue engineering to investigate the effect of pulsed mechanical stimulation on cell nutrition and cell orientation.
One of the major problems of perfusion systems is the formation of air bubbles in the passage of the fluid, which causes changes in local stress, blockage of the fluid path and increase the local flow rate. Using the bubble trap system, the bubbles created can be removed to some extent. Also, the use of oxygen delivery methods, such as the use of silicone membranes or tubes, reduces the rate of bubble formation in the fluid path.
Conclusion: Perfusion bioreactors are mostly used in tissue engineering due to their uniform distribution of nutrients as well as their ability to create a quasi-physiological environment for cell growth. In perfusion systems, it is possible to continuously control and monitor environmental and operational variables of the process such as component concentration, temperature, pressure and flow rate. These bioreactors increase mass transfer and, by applying shear stress stimuli, provide the physical signals necessary for cell differentiation and proliferation to function optimally. However, cell separation at high flow rates is one of their disadvantages. By optimizing the flow rate and combining forces such as rotation and perfusion, the performance of these bioreactors can be improved.
Keywords: Bioreactor, Perfusion, Tissue engineering, Mass transfer, Computational fluid dynamics