Bioreactors design operation and novel applications pdf

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Sacks, G. Engelmayr Jr. Hildebrand, J.

Bioreactor

Engineering design of microbioreactors MBRs and organ-on-chip OoC devices can take advantage of established design science theory, in which systematic evaluation of functional concepts and user requirements are analyzed. This is commonly referred to as a conceptual design.

This review article compares how common conceptual design principles are applicable to MBR and OoC devices. The complexity of this design, which is exemplified by MBRs for scaled-down cell cultures in bioprocess development and drug testing in OoCs for heart and eye, is discussed and compared with previous design solutions of MBRs and OoCs, from the perspective of how similarities in understanding design from functionality and user purpose perspectives can more efficiently be exploited.

The review can serve as a guideline and help the future design of MBR and OoC devices for cell culture studies. The engineering design of micro-bioreactors MBRs and Organ-on-Chips OoCs has attracted much attention in recent years [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].

The MBR derives its name from the bioengineering methodology of performing biological reactions in micro-scale reactor devices; OoC refers to the recreation of organs and tissues from the human body on or in a miniaturized device with a smaller volume than the original organ and with body-like fluids streaming around the cells in an in vivo-like fashion [ 8 , 9 , 10 ].

Despite this difference, many of the basic engineering principles coincide in the design of MBRs and OoCs. Probably due to that, the terms are used concurrently. For bioprocess development, the MBRs are considered valuable tools for accelerating development of new bioprocesses with microorganisms or mammalian cells as production organisms [ 11 , 12 ].

The culture of the manufacturing process is scaled-down to 1—10 mL volume of the MBR, and critical process parameters and media composition are systematically optimized [ 13 , 14 ]. The MBRs for bioprocess development have even been scaled down to the size of chips Bioreactor-on-a-Chip [ 15 ] and used for mimicking chemostat or turbidostat bioreactors with bacteria and yeast [ 15 , 16 , 17 , 18 ].

The increased yield and productivity of the large-scale process can be reached at a much earlier stage in the process development with this approach. With OoC devices, the aim is to facilitate the study of organ cell assemblies in vitro, under conditions that recreate in vivo conditions of the organ in the body for recapitulating time-related cellular behavior. The OoC device allows for the observation of cellular effects when exposed to drugs or other chemicals.

Successfully applied, this supports the investigation of safety pharmacology and toxicology, and, when possible, the efficacy of drug compounds [ 7 , 8 , 9 , 10 , 21 , 22 ]. However, other organs [ 26 , 27 , 28 , 29 ] have attracted almost the same interest, e.

This is of great interest, as are tumors-on-chips, which are also covered in this special issue [ 32 , 33 ]. Importantly, the possibility to correctly observe, monitor, and analyze the effects of the cells through imaging, sensors, and other analytical means, as well as by controlling the process in the process development MBR or OoC, are pivotal for all applications of MBRs.

The design of the fluidics and transport inside the reactor chamber and the mixing in the device are common design problems. This results in some very similar design solutions. Figure 1 illuminates the similarities and diversities of MBR and OoC device for various applications. Although the intended use and outcome of the devices differ Figure 1 A , the transformations by the biological components in the devices are similar Figure 1 B.

The common transformation process that occurs in every MBR device provides similar prerequisites for the design. The resulting design solutions, such as a rack of small MBR-containers with optical sensors placed at the bottom of each micro-vessel Figure 1 C ; the compact artificial liver bioreactors with intertwined hollow-fibers for liquid and gas transport Figure 1 D ; or small channels with an internal membrane for transepithelial electrical resistance measurement TEER for drug penetration studies, PDMS chips with double channels, and parallel channels Figure 1 E are all examples that share the general structure in Figure 1 B.

Consequently, the design of the devices should follow that frame. The similarities and diversities of micro-bioreactor design. Established conceptual design methodology [ 38 , 39 ] could therefore significantly facilitate the development process of new MBR and OoC devices. The established conceptual design methodology is based on approaching the design of a new product from a functional perspective in which the functionality of the product drives the development of the design.

In industrial design, conceptual methodology is widely applied to mechanical and electrical products [ 40 ]. However, in bioengineering it has been so far rarely used, with only a few examples on bioreactor scale-up [ 41 , 42 ], bioprocess configuration, monitoring and control [ 43 , 44 ], and stem cell production [ 45 , 46 ], but also recently for organ-on-chips [ 47 ].

In this review article, it is shown how the general conceptual design methodology can be applied to develop and improve the design of micro-bioreactors on a functional level. Two examples of conceptual design are shown to illuminate the similarities and differences in the design of MBR and OoC: 1 an MBR for production of hamster cells and 2 a heart-on-a-chip reactor for drug testing.

The conceptual design methodology is based on a systematic procedure to analyze the design objectives and, from these, conceive alternative design solutions that meet the objectives for a new product prototype [ 38 , 39 , 40 , 48 ]. The workflow in the development process in conceptual design starts with identifying the functions that are required to realize the user needs of the product and, from that, select and configure functional components that can effectuate user needs Figure 2.

Alternative configurations are compared with user needs and ranked versus user needs. This results in a preferred configuration. Once this choice is made, the functional components of the configuration are replaced with real physical components or objects.

This results in a blueprint for an initial prototyping, which then undergoes testing and is transferred to the manufacturing of the product [ 30 ]. The methodology is well-known in mechanical engineering. It is seldom applied in bioengineering, e. In the following, the general workflow in conceptual design when developing a MBR prototype is described.

The workflow in conceptual design when developing a new product prototype as suggested by several authors [ 30 , 31 , 32 ]. The steps are iterative and partly parallel to speed up the work in the design team. For achieving success with the conceptual design, a stringent and covering description of the design objective, or the design mission, is the starting point in the process of finding the appropriate design solution.

The description of the objective constrains the design. Indirectly, it also encircles existing or potential users [ 49 ]. Once the users are known, they can be interrogated about their actual needs and requirements on the design solution [ 50 ]. Generally, the user needs for MBRs and OoCs vary with the purpose of the targeted product, which results in different priorities as shown in Table 1.

The table elucidates the wide variation in character of needs and requirements that exist, in which some significantly impact the design, while others do not.

For example, a certain number of cells are necessary for recapitulating an in vivo function, which sets the minimal size of the MBR-unit; critical biomarker molecules or protein product, side-products are produced in amounts possible to measure, which sets another minimal limit for the number of cells required in the MBR-unit; distribution of oxygen and uptake of oxygen in the unit may also be requirements that constrain the design.

Other more specified user needs for an MBR related to the design objective could, for example, involve longevity of use of the MBR, generation of gradients in pO 2 and nutrients in the device, transformation rates of the cell culture, scalability of units, and flow-through rates. Such needs are highlighted by other authors in this special issue, e.

Once needs are identified and clearly described, they are also specified with target values or range of values. The target metrics may vary considerably. Table 2 gives examples for a liver-on-a-chip [ 47 ]. Note that specified values can be either quantitative or qualitative. A key activity in conceptual design is to describe and establish the structure of the transformation that the designed prototype should perform and what functions are required to perform the transformation.

This is done in a graphical representation of the transformation and functions Figure 3 A , a so-called Hubka-Eder map named after Vladimir Hubka — and Wolfgang Ernst Eder — , the originators of this representation [ 38 ]. The essential purpose of this map is 1 to define the transformation process, usually in the phases for preparation, main transformation, and finishing, that should take place in the designed device; and 2 to define the functions required for carrying out the transformation process [ 48 ].

The functions are structured into groups of systems, and these are further broken down into functional subsystems Figure 3 B.

In a mathematical formalism, this can be described as. The i index refers to main functional systems, which we divide into the biological systems, the technical systems, the information systems, the management systems, and the human systems necessary for carrying out the transformation process. To these systems, we also add the unknown surrounding environment, referred to as the active environment, which can influence the functions in ways we are not able to foresee. That could be biological variation, unpredictable sample background, or even influences associated with laws and regulations.

A Overall Hubka-Eder map showing the transformation process and functional systems; B a zoom-in of the biological and technical subsystems and their interactions in between and with the transformation process phases; and C the interaction matrix with assessed interaction effects between subsystems. The functional systems and sub-systems interact with the transformation process to drive it forward but can also interact with adjacent functional sub-systems. Understanding the effects of these interactions on the transformation process is the core for accomplishing a functional prototype and is fundamental for making important design decisions.

Figure 3 C shows a convenient way to represent these interaction effects by ordering them into an interaction matrix, IM :. The weights wi,j are values estimating the interaction strengths. These strengths are not precise measures and should only be seen as relative estimates for comparing each FSi,j.

When designing MBR devices, technical data from literature can often be helpful. The wealth of published data should, however, be carefully used and valued. The Hubka-Eder mapping and the interaction analysis facilitate identification of essential functional components necessary for the design of the prototype [ 38 ].

Figure 4 A shows a collection of 17 functional components suitable for the design of an MBR prototype, with the functional components grouped in the function systems from the HE-map. Note that a functional component is solely a conceptual object capable of carrying out the function, not a defined physical component, such as a valve or a pump. For example, a fluidic transporter only tells what you want the component to do, not if it is produced by pumping, using a syringe, or utilizing gravitational force.

Figure 4 B shows two examples of configurations from the 17 functional components. In one configuration I , cells are transferred to a temperature-controlled space in which the biological systems are preserved in several separately contained and temperature-controlled units with sensor functions. In the other configuration II , all units are placed in the same temperature-controlled unit, and sensors are shared between the contained cell units. Theoretically, the 17 functional components in Figure 4 can be combined in a multitude of configurations, most of them unrealistic, but a few are realistic and worth investigating further.

A Biological green , technical blue , and information red functional components required in an MBR device as identified from the functional subsystems in the HE-map in Figure 3 ; B Two examples of configurations from these functional components in which two MBR units are included in the prototype design.

The configuration alternatives generated from the functional components should now be compared and assessed versus the user specification target values in Table 2 [ 40 ]. Initially, a relatively high number of configuration alternatives can be assessed by a rough screening 20—30 configurations depending on number of components. By that, the number of configurations can be reduced to less than 10, and these can be assessed more thoroughly. Typically, the configuration alternatives can be limited to five or six.

We rank their assumed effect on the target specification value; either this is quantitative or qualitative. The ranking is at this stage relative, but could be quantified more exactly, e. This will require experimental evidence, e.

Table 3 shows an example of estimated ranking scores for four configuration alternatives. A four-level ranking as shown in the example is sufficient to discriminate the configurations versus the specification values.

In Table 3 , alternative 2 gets the highest score and is chosen for further development towards a prototype.

In the table it is also possible to introduce weight factors to tune the importance of each need in relation to the design objective. For example, low price may have much more impact than size. The balance of the weights is decisive for the final ranking score. A design team must consequently be aware of this and be cautious of how they treat values. However, if they do this, it will become an efficient means with which to perform sensitivity and risk analysis at this early stage of the design.

Example of ranking of design alternatives versus target specification metrics 1. Once the functionally most feasible design alternative has been selected from the scoring of the user needs, the real physical components replace the functional components [ 48 ].

Bioreactors for tissue engineering: principles, design and operation

Biochemical Engineering and Biotechnology, 2nd Edition, outlines the principles of biochemical processes and explains their use in the manufacturing of every day products. The author uses a diirect approach that should be very useful for students in following the concepts and practical applications. This book is unique in having many solved problems, case studies, examples and demonstrations of detailed experiments, with simple design equations and required calculations. The book is appropriate as a college and university text book for undergraduate senior courses and postgraduate course. Students and research scientists in biochemical engineering and biological sciences will find this reference particularly useful for gaining an overview of the subject and planning research activities. It is also useful for research institutes and postgraduates who are involved in practical research in biochemical engineering and biotechnology. He is an educated scholar from University of Arkansas, USA with strong background in biological processes.

A bioreactor refers to any manufactured device or system that supports a biologically active environment. This process can either be aerobic or anaerobic. These bioreactors are commonly cylindrical, ranging in size from litres to cubic metres, and are often made of stainless steel. On the basis of mode of operation, a bioreactor may be classified as batch , fed batch or continuous e. An example of a continuous bioreactor is the chemostat.

Engineering design of microbioreactors MBRs and organ-on-chip OoC devices can take advantage of established design science theory, in which systematic evaluation of functional concepts and user requirements are analyzed. This is commonly referred to as a conceptual design. This review article compares how common conceptual design principles are applicable to MBR and OoC devices. The complexity of this design, which is exemplified by MBRs for scaled-down cell cultures in bioprocess development and drug testing in OoCs for heart and eye, is discussed and compared with previous design solutions of MBRs and OoCs, from the perspective of how similarities in understanding design from functionality and user purpose perspectives can more efficiently be exploited. The review can serve as a guideline and help the future design of MBR and OoC devices for cell culture studies. The engineering design of micro-bioreactors MBRs and Organ-on-Chips OoCs has attracted much attention in recent years [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].

Control and Analytics

Monitoring and control is key in bioprocess development. Critical process parameters define the process environment for optimum cell growth and high-titer production. Control loops for temperature, dissolved oxygen DO , pH, agitation, and level are routinely applied in bioreactor systems. Process Analytical Technology PAT provides deeper insights into the metabolic state of the culture and facilitates automation. Through the seamless integration of autosamplers and analyzers such as biomass monitors, cell counters, mass spectrometers, and HPLC, process engineers advance their development and work in line with Quality-by-Design QbD guidelines.

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In this expert handbook both the topics and contributors are selected so as to provide an authoritative view of possible applications for this new technology. The result is an up-to-date survey of current challenges and opportunities in the design and operation of bioreactors for high-value products in the biomedical and chemical industries. Combining theory and practice, the authors explain such leading-edge technologies as single-use bioreactors, bioreactor simulators, and soft sensor monitoring, and discuss novel applications, such as stem cell production, process development, and multi-product reactors, using case studies from academia as well as from industry.

Bioreactors. Design, Operation and Novel Applications

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Bioreactors for Tissue Engineering: Principles, Design and Operation - PDF Free Download

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