Controlled gas exchange in whole lung bioreactors

Abstract

In cellular, tissue-level or whole organ bioreactors, the level of dissolved oxygen is one of the most important factors requiring control. Hypoxic environments may lead to cellular apoptosis, while hyperoxic environments may lead to cellular damage or dedifferentiation, both resulting in loss of overall tissue function. This manuscript describes the creation, characterization and validation of a bioreactor system that can control oxygen delivery based on real-time metabolic demand of cultured whole lung tissue. A mathematical model describing and predicting gas exchange within the tunable bioreactor system is developed. In addition, the inherent gas exchange properties of the bioreactor and the inherent oxygen consumption rates of native rat lungs are determined, thereby providing a quantitative relationship between system parameters and levels of dissolved oxygen. Finally, the mathematical model is validated during whole lung culture under a range of system parameters. The system presented here provides a quantitative relationship between the concentration of dissolved oxygen, tissue oxygen consumption rates, and controllable system parameters that introduce gasses into the bioreactor. This relationship not only enables the maintenance of constant levels of dissolved oxygen throughout a culture period during which cells are replicating, but also provides noninvasive and real-time estimation of the metabolic and proliferative states of native or engineered lung tissue simply through dissolved oxygen measurements.

Ex Vivo Perfusion Using a Mathematical Modeled, Controlled Gas Exchange Self-Contained Bioreactor Can Maintain a Mouse Kidney for Seven Days

“…The benchtop design is good for experimental observations but limits them to short-term experiments as sterility is an issue and the units are cumbersome to operate and expensive [ 6 ]. Successful bioreactors that aid in the study of rodent ovaries, heart, lungs, liver and kidneys have been developed [ 7 , 8 , 9 , 10 ] but use rat organs. There are few studies using mouse organs, although mouse is the primary small-animal model with 100′s of established models of human kidney disease available [ 11 ].…”

Critical parameters and procedures for anaerobic cultivation of yeasts in bioreactors and anaerobic chambers

“… 2015 ; Engler et al . 2018 ) are extremely efficient, affordable and practical devices for deoxygenating the medium feed of continuous-cultivation systems (Fig. 5 ).…”

Advances in bioreactors for lung bioengineering: From scalable cell culture to tissue growth monitoring

“…A research group introduced a bioreactor delivering the oxygen-based on real-time metabolic demands in whole lung culture, resulting in controlled gas exchange. This bioreactor estimated the metabolic and proliferative states of native or engineered lung tissues in a real-time manner (Engler et al, 2018).…”

“…For decellularization and recellularization of lungs, bioreactor systems with different sizes for small rodents (Engler et al, 2019;Laranger et al, 2018;Obata et al, 2019) to human-scale models (Balestrini et al, 2015(Balestrini et al, , 2016Nichols et al, 2017) were used. Monitoring bioreactors were utilized to measure biological parameters of the cells within the engineered tissues (e.g., O 2 and CO 2 levels, glucose consumption, lactate production, and pH values), helping control and optimize the culture conditions to manage and determine the maturation time of the bioengineered lungs before transplantation (Engler et al, 2018;Mahfouzi et al, 2018). Ex vivo lung perfusion (EVLP) systems were also applied to recover and maintain lungs ex vivo for transplantation for several hours (Spratt et al, 2017(Spratt et al, , 2018(Spratt et al, , 2020Warnecke et al, 2012).…”