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Optical Redox Probe for Continuous Metabolic Monitoring during Natural Products Bioprocessing

用于天然产品生物加工过程中连续代谢监测的光学氧化还原探针

基本信息

批准号：
10687154
负责人：
Youbo Zhao
金额：
$ 87.35万
依托单位：
PHYSICAL SCIENCES, INC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687154
关键词：
Academia Address Advanced Development Agitation Amino Acids Anabolism Biochemical Pathway Biological Products Biomanufacturing Bioreactors Cell Culture System Cells Cellular Metabolic Process Collaborations Complex Consumption Cytometry Data Development Excision Fatty Acids Fermentation Fiber Flavin-Adenine Dinucleotide Fluorescence Generations Goals Health Hour Hybrids Industry Journals Kinetics Label Learning Marketing Massachusetts Measurement Measures Medicine Metabolic Metabolism Methods Microbe Modeling Monitor Natural Products Nature Nicotinamide adenine dinucleotide Noise Optics Oxidation-Reduction Pathway interactions Patients Peer Review Performance Periodicals Pharmacologic Substance Phase Physiologic pulse Physiological Physiology Plants Process Production Productivity Publications Research Risk Sampling Sensitivity and Specificity Signal Transduction Site Source Steroids System Technology Terpenes Testing Theoretical model Time Universities Update bioprocess commercialization cost design discrete time drug quality experimental study extracellular feeding fluorophore improved industry partner instrument large scale production metabolomics microorganism culture microorganism metabolism miniaturize natural flow novel operation physical science polyketides process improvement programs prototype research and development sensor sensor technology success symposium temporal measurement two-photon

项目摘要

Project Summary/Abstract Almost half of the medicines on the market are natural products including polyketides, fatty acids, amino acids, terpenoids and steroids. Though many of the natural products are discovered in plants, mass production of these molecules relies on culturing microorganisms in bioreactors. However, it is often a challenge to develop and maintain high biomanufacturing productivity and yield to enable low-cost and high- quality production at large scales. One unmet need is an ability to rapidly and accurately measure the physiological status of microbes at the cellular level within bioreactors. Measuring the cellular metabolic state, especially energetic and redox parameters, is key to developing improved biosynthesis processes and to guiding feeding strategies and other operational actions. Due to the complex nature of bioreactor cell culture systems, currently the capability of measuring cellular metabolic parameters in real time is unavailable, and metabolic assessment relies on time-consuming, periodic removal of culture samples for off-line analysis. During this R&D program, Physical Sciences Inc. (PSI), in collaboration with the University of Massachusetts Lowell (UML) and Northeastern University (NEU), will develop a novel two-photon excitation (TPE) fluorescence redox sensor for on-line, real-time measurement of cell metabolism in bioreactors for natural products fermentation. A miniaturized optical probe will be developed that can be sterilized and inserted into bioreactor cultures for continuous measurement of dynamic changes of important intracellular metabolites. The technology is equivalent to an online cytometer within the bioreactor, providing critical cellular-level physiology data that would otherwise be only available from off-line measurements. The intracellular redox ratio will be monitored using the autofluorescence of endogenous fluorophores, without the need (but not excluding the option) for exogenous fluorescence labeling. During the Phase I program, the PSI led team successfully demonstrated the feasibility of the proposed technology. A Gen-I prototype redox sensor was fabricated and tested during continuous metabolism measurements in operational bioreactors, mitigating the critical technical risks of the proposed Phase II research. During the Phase II program, the research effort will be focused on optimizing the technology, demonstrating its value in advancing biomanufacturing process development and operations, and preparing for commercialization. In particular, a Gen-II prototype with significantly improved signal to noise ratio and system robustness will be fabricated. The Gen-II instrument will then be tested in a large-number of bioreactor operations to demonstrate how the new real-time cellular metabolism data will be utilized to guide the development and operation of novel and more effective bioreactor processes for improved product yield. The experimental data will also be input into theoretical bioprocess models to promote improved understanding and control of the processes.

项目总结/文摘