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BioSMART: BIOreactor Spatial Mapping and Actuation in Real Time

BioSMART：生物反应器实时空间映射和驱动

基本信息

批准号：
EP/W024969/1
负责人：
Christopher Rowlands
金额：
$ 128.93万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FW024969%2F1
关键词：
BioSMART BIOreactor Spatial Mapping Actuation

项目摘要

Many drugs and chemicals we have today are made not in chemical plants, but in bioreactors: vessels containing microbes or other cells which can create the chemical we want. We do this because using living cells to create complex chemicals can be much cheaper in terms of energy, raw materials and the cost of making the plant itself (which does not need to operate at high temperature and pressure as some chemical plants do). Nevertheless, bioreactors are harder to use than their chemical plant cousins, because living cells are sensitive to their environment in a range of complex and difficult-to-model ways. The only sensible way to make sure that the bioreactor is working at maximum capacity is to watch what is going on during the reaction.In this project we want to, for the first time, monitor the conditions of cells throughout the bioreactor by using the cells themselves to tell us what is what is going on. We can do this by genetically modifying the cells to change their physical properties based on their local environment. We call these genetically-modified cells biosensors, and in our case they report their condition by fluorescence: making a protein which glows when you shine light on it. While studies have demonstrated the development of biosensors and their benefits in bioprocessing, so far the implementation of biosensors in industrial processes has been hampered by a lack of infrastructure for their use. This is because most analytical techniques to date have not been living, but rather based on chemical or physical development of signals. In order to really capitalise on the enhanced sensitivity and specificity of biosensors, development of hardware and data analysis tools for integrating them into industrial bioreactors is needed. This proposal seeks to fill this gap.Monitoring the fluorescent glow is a challenge; the bioreactor itself isn't nice and transparent, but murky and turbid. We can't just look through it, because light from the outside will scatter (or bounce) multiple times before it gets out again. Fortunately, there is a technique called Fluorescence Diffuse Optical Tomography (fDOT) which can account for scattered light. It cannot resolve as small features as a microscope, but in a bioreactor this isn't important, as centimeter-scale resolution is enough. We will build a system that can monitor the whole bioreactor using fDOT, by shining a laser at different points on the reactor surface and watching the resulting glow from the cells on all sides; by taking measurements from lots of different locations and using a suitable computer algorithm, we can get a 3D model of how the glowing cells are distributed. With this information, we can then use modelling to predict the cell behaviour and to automatically control the bioreactor conditions to improve production.As a demonstration, we will focus on monitoring the buildup of lactic acid which is a byproduct of anaerobic (oxygen-poor) reaction conditions; excess lactic acid is toxic, and can limit the performance of (or even kill) the cells that produce it. By engineering the cells to glow based on how much lactic acid there is nearby, we can monitor the reaction and either increase the amount of oxygen added to the reaction, stir the tank, or even redesign the reactor itself to avoid local differences in the reaction conditions. The case of lactic acid is just an example; future cells might report changes in temperature, shear stress, oxygenation or any other parameter, with a different-coloured glow for each.Overall, this project represents the first step towards a new frontier where the cells in a bioreactor not only produce the chemicals we want, but tell us what is going wrong in the reaction and how to fix it. The result is a reactor that can make complex chemicals much more cheaply, and given how much of our modern world relies on these chemicals, that can have subtle but pronounced benefits throughout the global economy.

我们今天拥有的许多药物和化学品不是在化工厂生产的，而是在生物反应器中生产的：含有微生物或其他细胞的容器可以产生我们想要的化学物质。我们这样做是因为使用活细胞来制造复杂的化学物质在能源、原材料和制造工厂本身的成本方面要便宜得多（不需要像一些化工厂那样在高温高压下运行）。然而，生物反应器比化学反应器更难使用，因为活细胞以一系列复杂且难以建模的方式对环境敏感。确保生物反应器以最大容量工作的唯一明智的方法是观察反应过程中发生了什么。在这个项目中，我们想，第一次，监测整个生物反应器中细胞的状况，通过细胞本身来告诉我们发生了什么。我们可以通过基因改造细胞来改变它们的物理特性，这是基于它们所在的环境。我们称这些基因修饰的细胞为生物传感器，在我们的例子中，它们通过荧光来报告它们的状况：当你光照它时，它会产生一种发光的蛋白质。虽然研究已经证明了生物传感器的发展及其在生物加工中的好处，但到目前为止，由于缺乏使用生物传感器的基础设施，生物传感器在工业过程中的实施受到阻碍。这是因为到目前为止，大多数分析技术都不是活的，而是基于信号的化学或物理发展。为了真正利用生物传感器增强的灵敏度和特异性，需要开发硬件和数据分析工具，将它们集成到工业生物反应器中。本提案旨在填补这一空白。监测荧光是一个挑战；生物反应器本身并不是透明的，而是浑浊的。我们不能只是透过它看，因为从外面来的光在再次出来之前会散射（或反弹）多次。幸运的是，有一种叫做荧光漫射光学断层扫描（fDOT）的技术可以解释散射光。它不能像显微镜那样分辨小的特征，但在生物反应器中这并不重要，因为厘米级的分辨率就足够了。我们将建立一个系统，可以监测整个生物反应器使用fDOT，通过激光照射在反应器表面的不同点，并观察从所有的细胞产生的光；通过从许多不同的位置进行测量，并使用合适的计算机算法，我们可以得到发光细胞分布的3D模型。有了这些信息，我们就可以使用建模来预测细胞的行为，并自动控制生物反应器的条件，以提高产量。作为示范，我们将重点监测乳酸的积累，乳酸是厌氧（缺氧）反应条件下的副产物；过量的乳酸是有毒的，可以限制（甚至杀死）产生它的细胞的性能。通过根据附近乳酸的多少来设计细胞发光，我们可以监控反应，或者增加加入反应的氧气量，搅拌水箱，甚至重新设计反应器本身，以避免反应条件的局部差异。乳酸只是一个例子；未来的细胞可能会报告温度、剪切应力、氧合或任何其他参数的变化，每种变化都会发出不同颜色的光。总的来说，这个项目代表了迈向新前沿的第一步，生物反应器中的细胞不仅可以产生我们想要的化学物质，还可以告诉我们反应中哪里出了问题以及如何解决问题。其结果是一个可以以更低的成本生产复杂化学品的反应堆，考虑到我们的现代世界对这些化学品的依赖程度，它可以在整个全球经济中产生微妙但明显的好处。