Stem cell biomanufacturing under uncertainty: A case study in optimizing red blood cell production

Abstract

As breakthrough cellular therapy discoveries are translated into reliable, commercializable applications, effective stem cell biomanufacturing requires systematically developing and optimizing bioprocess design and operation. This article proposes a rigorous computational framework for stem cell biomanufacturing under uncertainty. Our mathematical tool kit incorporates: high‐fidelity modeling, single variate and multivariate sensitivity analysis, global topological superstructure optimization, and robust optimization. The advantages of the proposed bioprocess optimization framework using, as a case study, a dual hollow fiber bioreactor producing red blood cells from progenitor cells were quantitatively demonstrated. The optimization phase reduces the cost by a factor of 4, and the price of insuring process performance against uncertainty is approximately 15% over the nominal optimal solution. Mathematical modeling and optimization can guide decision making; the possible commercial impact of this cellular therapy using the disruptive technology paradigm was quantitatively evaluated. © 2017 American Institute of Chemical Engineers AIChE J, 64: 3011–3022, 2018

Bayesian Multiobjective Optimisation With Mixed Analytical and Black-Box Functions: Application to Tissue Engineering

“…We could create a single-objective optimisation problem by setting a monetary value on the neotissue produced in the bioreactor, and optimise the design variables by maximising the difference between the monetary reward of the neotissue and the production cost, e.g. as in growing red blood cells [35], [36]. This would be equivalent to scalarisation, which is described later in this section.…”

Ceramic Hollow Fibre Constructs for Continuous Perfusion and Cell Harvest from 3D Hematopoietic Organoids

“…Although the HFs could only reach a 97% dead-end separation efficiency, the filtered suspensions contained a greater ratio of mononuclear to enucleated cells (5 : 1), more relevant to current hematopoietic culture than standard peripheral blood leukoreduction (1 : 1000), where higher MNC contents could lead to fouling. Of these leukoreduction methods, HF filters can be uniquely incorporated within long-term 3D cultures to filter nutrients and cells [ 19 , 20 , 26 ].…”

“…However, such HEMA cultures inoculate rare CB CD34 + MNCs which are expanded at densities beneath 5 × 10 6 cells/mL. HEMA cultures require large medium volumes, abnormally high concentrations of expensive cytokines, and production costs 1-2 orders of magnitude above donated RBC unit costs [ 2 , 20 , 26 ]. A recently described immortalized erythroblast line could mitigate cell source limitations by providing unlimited RBC generation [ 42 ], while medium requirements and RBC harvest could be made more economically viable using proposed HFBR bioprocessing strategies, where CD235a enucleation rate would be a critical parameter for future study.…”

Mechanobiological conceptual framework for assessing stem cell bioprocess effectiveness

“…Understanding the prevalence of pre-existing intrinsic and extrinsic variability over external noise is important for developing key indicators to identify and predict the bioprocess variability. The phenomenon of "intrinsic disorder" has been widely studied in bioprocess conditions, and understanding and controlling the sources of variability are anticipated to play important roles in improving bioprocess control and optimization (Kim and Kino-oka, 2020b;Misener et al, 2018). Indeed, it has been shown that the phenotypic variability among stem cells can contribute to the inherent differences resulting from donor-dependent variability as well as changes induced during cellular reprogramming and expansion and cell handling processes such as passaging, freezing, or thawing (Kim and Kino-oka, 2018).…”