Predictive macroscopic modeling of Chinese hamster ovary cells in fed-batch processes

This thesis focuses on developing a systematic modeling method that can capture the essential features for prediction of cell metabolism, growth and monoclonal antibody (mAb) production in Chinese Hamster Ovary (CHO) cells. In a first step all specific consumption rates are calculated based on time courses of extracellular metabolites, viable cell density and mAb. Then the metabolic phases within which the metabolic pseudo-steady state approximation is verified are identified. In a third step, all metabolic rates are expressed as a function of the specific growth rate within each metabolic phase. We have applied this method to a set of small bioreactor data and have shown that the model obtained can predict specific conversion rates both small and also at large scale. In the second part of this thesis, a kinetic model of the cell growth has been developed. Together with previously described methodology, this kinetic model results in a predictive metabolic model for each experimental cell growth data are not required. The kinetic model is based on Monod kinetics with a few modifications such as a varying the maximum specific growth rate as a function of the integral viable cell density. The full kinetic model can be used off line to design optimal feeding profiles. The results of this thesis demonstrate that rich knowledge can be derived from macroscopic data that can then be used to predict new production conditions in an industrial environment at small and large scale.Der Schwerpunkt dieser Dissertation liegt auf der systematischen Entwicklung Modellen für die Vorhersage des zellulären Stoffwechsels, des Wachstums und der Produktion von monoklonalen Antikörpern (mAb) in Kulturen von Chinesischen Hamster-Ovarzellen (CHO). Zunächst wurden mit segmentierter linearer Regression metabolischer Phasen identifiziert. Diese Identifizierung beruht auf der Annahme eines pseudo-stationären Zustands und somit, dass in einer Phase alle Raten linear miteinander korreliert waren. Die spezifischen Raten wurden aus den Zeitverläufen der Konzentrationen der Metabolite und des mAb sowie der Lebendzellzahl bestimmt. Durch die Korrelation konnten alle Raten über die Wachstumsrate im 2 L und im 2000 L Maßstab berechnet werden. Danach wurde ein kinetisches Modell des Wachstums der Zellen etabliert, was die Vorhersage aller Raten auch in fed-batch Kulturen erlaubt. Die Kinetik basiert auf der Monod-Kinetik modifiziert mit einer variablen maximalen spezifischen Wachstumsrate. Das kinetische Modell erlaubt eine rechnerische Optimierung der Substratzuführung für eine maximale Produktion. Damit wurde gezeigt, dass aus makroskopischen Daten, d.h. ohne intrazelluläre Messungen, wesentliche Informationen erhalten werden können, mit denen neue Experimente in einem industriellen Umfeld vorhergesagt werden können. Diese innovative und systematische Vorgangsweise eröffnet neue Perspektiven für die Reduzierung von Kosten und für eine Beschleunigung der Prozessentwicklung

From product microheterogeneity to homogeneity using integrated modeling methodology and new cell culture component

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Novel modeling methodology to predict product quality and cell culture performance in fed-batch and perfusion cultures

The acceleration of biopharmaceutical process development is difficult when traditional experience-based sequential approaches are used. As a result, fully optimized and well understood cell culture processes prior to scale-up are rare. Here we show that an accurate, scalable and simple model able to predict cell growth, cell metabolism, titer and some product quality attributes will significantly accelerate process development, improve process development outcomes and reduce development and production costs. Please click Additional Files below to see the full abstract

Predictive macroscopic models of cell growth, metabolism and monoclonal antibody production of fed-batch processes at various scales

Recently, the pharmaceutical industry is increasingly focusing on early drug development which comes with increasing constraints to accelerate process development, reduce costs and demonstrate a deep understanding cell culture processes. However, cellular metabolism is very complex and by far not fully understood. Cells can be cultivated in various types of bioreactors applying sophisticated feeding strategies mostly based on experience and series of experiments. Modern systems biology promises modeling of such processes on the basis of a system-wide understanding of cellular processes but is still unable to deliver predictive models in due time at reasonable cost. Practically applicable, predictive models are highly demanded in industry for the purpose of process optimization and control. To this end, we developed a systematic methodology for metabolic and cell growth modeling that is directly applicable in an industrial environment. We demonstrate that the models developed are able to predict a wide range of new experimental cell culture conditions. Please click Additional Files below to see the full abstract

Bioprocess intensification and optimisation using macroscopic predictive models of cell culture processes

CHO cells, modeling, perfusion, ATF, segmented linear mode

Energy-aware task scheduling and offloading using deep reinforcement learning in SDN-enabled IoT network

5G mobile network services have made tremendous growth in the IoT network. As a result, a counters number of battery-powered IoT devices are deployed to serve diverse scenarios, e.g., smart cities, autonomous farming, smart manufacturing, to name but a few. In this context, energy consumption became one of the most critical concerns in interconnecting smart IoT devices in such scenarios. Additionally, whenever these IoT devices are distributed in space and time-evolving, they are expected to deliver high volume data scalably/predictably while minimizing end-to-end latency. Furthermore, edge IoT nodes often face the biggest hurdle of performing optimal resource distribution and achieving high-performance levels while coping with task handling, energy conservation, and ultra-reliable low-latency variability. This paper investigates an energy-aware and low-latency oriented computing task scheduling problem in a Software-Defined Fog-IoT Network. We formulate the online task assignment and scheduling problem as an energy-constrained Deep Q-Learning process as a kickoff. The latter strives to minimize the network latency while ensuring energy efficiency by saving battery power under the constraints of application dependence. Then, given the task arrival process, we introduce a deep reinforcement learning (DRL) approach for dynamic task scheduling and assignment in SDN-enabled edge networks. We conducted comprehensive experiments and compared the presented algorithm to three pioneering deep learning algorithms (i.e., deterministic, random, and A3C agents). Extensive simulation results demonstrated that our proposed solution outperforms these algorithms. Additionally, we highlight the characterizing feature of our design, energy-awareness, as it offers better energy-saving by up to 87% compared against the other approaches. We have shown that the offloading scheme could perform more tasks with the available battery power by up to 50% more minor time delay. Our results support our claims that the solution we propose can readily be used to dynamically optimize task scheduling and assignment of complex jobs with task dependencies in distributed Fog IoT networks

Accurate prediction of international trade flows: Leveraging knowledge graphs and their embeddings

Knowledge representation (KR) is vital in designing symbolic notations to represent real-world facts and facilitate automated decision-making tasks. Knowledge graphs (KGs) have emerged so far as a popular form of KR, offering a contextual and human-like representation of knowledge. In international economics, KGs have proven valuable in capturing complex interactions between commodities, companies, and countries. By putting the gravity model, which is a common economic framework, into the process of building KGs, important factors that affect trade relationships can be taken into account, making it possible to predict international trade patterns. This paper proposes an approach that leverages Knowledge Graph embeddings for modeling international trade, focusing on link prediction using embeddings. Thus, valuable insights are offered to policymakers, businesses, and economists, enabling them to anticipate the effects of changes in the international trade system. Moreover, the integration of traditional machine learning methods with KG embeddings, such as decision trees and graph neural networks are also explored. The research findings demonstrate the potential for improving prediction accuracy and provide insights into embedding explainability in knowledge representation. The paper also presents a comprehensive analysis of the influence of embedding methods on other intelligent algorithms