Laboratory robotics

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Laboratory robots doing acid digestion chemical analysis. Argon robot acid digestion.jpg
Laboratory robots doing acid digestion chemical analysis.

Laboratory robotics is the act of using robots in biology, chemistry or engineering labs. For example, pharmaceutical companies employ robots to move biological or chemical samples around to synthesize novel chemical entities or to test pharmaceutical value of existing chemical matter. [1] [2] Advanced laboratory robotics can be used to completely automate the process of science, as in the Robot Scientist project. [3]

Contents

Laboratory processes are suited for robotic automation as the processes are composed of repetitive movements (e.g., pick/place, liquid/solid additions, heating/cooling, mixing, shaking, and testing). Many laboratory robots are commonly referred as autosamplers, as their main task is to provide continuous samples for analytical devices.

History

The first compact computer controlled robotic arms appeared in the early 1980s, and have continuously been employed in laboratories since then. [4] These robots can be programmed to perform many different tasks, including sample preparation and handling.

Yet in the early 1980s, a group led by Masahide Sasaki, from Kochi Medical School, introduced the first fully automated laboratory employing several robotic arms working together with conveyor belts and automated analyzers. [4] [5] The success of Sasaki's pioneer efforts made other groups around the world to adopt the approach of Total Laboratory Automation (TLA).

Despite the undeniable success of TLA, its multimillion-dollar cost prevented that most laboratories adopted it. [6] Also, the lack of communication between different devices slowed down the development of automation solutions for different applications, while contributing to keeping costs high. Therefore, the industry attempted several times to develop standards that different vendors would follow in order to enable communication between their devices. [6] [7] However, the success of this approach has been only partial, as nowadays many laboratories still do not employ robots for many tasks due to their high costs.

Recently, a different solution for the problem became available, enabling the use of inexpensive devices, including open-source hardware, [8] to perform many different tasks in the laboratory. This solution is the use of scripting languages that can control mouse clicks and keyboard inputs, like AutoIt. [9] This way, it is possible to integrate any device by any manufacturer as long as they are controlled by a computer, which is often the case.

Another important development in robotics which has important potential implications for laboratories is the arrival of robots that do not demand special training for their programming, like Baxter, the robot.

Applications

Low-cost laboratory robotics

Low-cost robotic arm used as an autosampler. Low-cost robotic arm employed as an autosampler.jpg
Low-cost robotic arm used as an autosampler.

The high cost of many laboratory robots has inhibited their adoption. However, currently there are many robotic devices that have very low cost, and these could be employed to do some jobs in a laboratory. For example, a low-cost robotic arm was employed to perform several different kinds of water analysis, without loss of performance compared to much more expensive autosamplers. [10] Alternatively, the autosampler of a device can be used with another device, [9] thus avoiding the need for purchasing a different autosampler or hiring a technician for doing the job. The key aspects to achieve low-cost in laboratory robotics are 1) the use of low-cost robots, which become more and more common, and 2) the use of scripting, which enables compatibility between robots and other analytical equipment. [11]

Robotic, mobile laboratory operators and remote-controlled laboratories

In July 2020 scientists reported the development of a mobile robot chemist and demonstrate that it can assist in experimental searches. According to the scientists their strategy was automating the researcher rather than the instruments – freeing up time for the human researchers to think creatively – and could identify photocatalyst mixtures for hydrogen production from water that were six times more active than initial formulations. The modular robot can operate laboratory instruments, work nearly around the clock, and autonomously make decisions on his next actions depending on experimental results. [12] [13]

There is ongoing development of "remote controlled laboratories" that automatically perform many life sciences experiments per day and can be operated, including in collaboration, from afar. [14]

Pharmaceutical applications

One major area where automated synthesis has been applied is structure determination in pharmaceutical research. Processes such as NMR and HPLC-MS can now have sample preparation done by robotic arm. [15] Additionally, structural protein analysis can be done automatically using a combination of NMR and X-ray crystallography. Crystallization often takes hundreds to thousands of experiments to create a protein crystal suitable for X-ray crystallography. [16] An automated micropipet machine can allow nearly a million different crystals to be created at once, and analyzed via X-ray crystallography.

Reproducibility verification

This section is an excerpt from Replication crisis § Semi-automated.[ edit ]
"The overall process of testing the reproducibility and robustness of the cancer biology literature by robot. First, text mining is used to extract statements about the effect of drugs on gene expression in breast cancer. Then two different teams semi-automatically tested these statements using two different protocols, and two different cell lines (MCF7 and MDA-MB-231) using the laboratory automation system Eve." Semi-automated testing of reproducibility and robustness of the cancer biology literature by robot.jpg
"The overall process of testing the reproducibility and robustness of the cancer biology literature by robot. First, text mining is used to extract statements about the effect of drugs on gene expression in breast cancer. Then two different teams semi-automatically tested these statements using two different protocols, and two different cell lines (MCF7 and MDA-MB-231) using the laboratory automation system Eve."
Researchers demonstrated a way of semi-automated testing for reproducibility: statements about experimental results were extracted from, as of 2022 non-semantic, gene expression cancer research papers and subsequently reproduced via robot scientist "Eve". [17] [18] Problems of this approach include that it may not be feasible for many areas of research and that sufficient experimental data may not get extracted from some or many papers even if available.

Diagnostic testing for pathogens

For example, there are robots that are used to analyze swabs from patients to diagnose COVID-19. [19] [20] [21] Automated robotic liquid handling systems have been or are being built for lateral flow assays. It minimizes hands-on time, maximizes experiment size, and enables improved reproducibility. [22]

Biological laboratory robotics

An example of pipettes and microplates manipulated by an anthropomorphic robot (Andrew Alliance) Automated pipetting system using manual pipettes.jpg
An example of pipettes and microplates manipulated by an anthropomorphic robot (Andrew Alliance)

Biological and chemical samples, in either liquid or solid state, are stored in vials, plates or tubes. Often, they need to be frozen and/or sealed to avoid contamination or to retain their biological and/or chemical properties. Specifically, the life science industry has standardized on a plate format, known as the microtiter plate, [23] to store such samples.

The microtiter plate standard was formalized by the Society for Biomolecular Screening in 1996. [24] It typically has 96, 384 or even 1536 sample wells arranged in a 2:3 rectangular matrix. The standard governs well dimensions (e.g. diameter, spacing and depth) as well as plate properties (e.g. dimensions and rigidity).

A number of companies have developed robots to specifically handle SBS microplates. Such robots may be liquid handlers which aspirates or dispenses liquid samples from and to these plates, or "plate movers" which transport them between instruments.

Other companies have pushed integration even further: on top of interfacing to the specific consumables used in biology, some robots (Andrew [25] by Andrew Alliance, see picture) have been designed with the capability of interfacing to volumetric pipettes used by biologists and technical staff. Essentially, all the manual activity of liquid handling can be performed automatically, allowing humans spending their time in more conceptual activities.

Instrument companies have designed plate readers which can carry out detect specific biological, chemical or physical events in samples stored in these plates. These readers typically use optical and/or computer vision techniques to evaluate the contents of the microtiter plate wells.

One of the first applications of robotics in biology was peptide and oligonucleotide synthesis. One early example is the polymerase chain reaction (PCR) which is able to amplify DNA strands using a thermal cycler to micromanage DNA synthesis by adjusting temperature using a pre-made computer program. Since then, automated synthesis has been applied to organic chemistry and expanded into three categories: reaction-block systems, robot-arm systems, and non-robotic fluidic systems. [26] The primary objective of any automated workbench is high-throughput processes and cost reduction. [27] This allows a synthetic laboratory to operate with a fewer number of people working more efficiently.

Combinatorial library synthesis

Robotics have applications with combinatorial chemistry which has great impact on the pharmaceutical industry. The use of robotics has allowed for the use of much smaller reagent quantities and mass expansion of chemical libraries. The "parallel synthesis" method can be improved upon with automation. The main disadvantage to "parallel-synthesis" is the amount of time it takes to develop a library, automation is typically applied to make this process more efficient.

The main types of automation are classified by the type of solid-phase substrates, the methods for adding and removing reagents, and design of reaction chambers. Polymer resins may be used as a substrate for solid-phase. [28] It is not a true combinatorial method in the sense that "split-mix" where a peptide compound is split into different groups and reacted with different compounds. This is then mixed back together split into more groups and each groups is reacted with a different compound. Instead the "parallel-synthesis" method does not mix, but reacts different groups of the same peptide with different compounds and allows for the identification of the individual compound on each solid support. A popular method implemented is the reaction block system due to its relative low cost and higher output of new compounds compared to other "parallel-synthesis" methods. Parallel-Synthesis was developed by Mario Geysen and his colleagues and is not a true type of combinatorial synthesis, but can be incorporated into a combinatorial synthesis. [29] This group synthesized 96 peptides on plastic pins coated with a solid support for the solid phase peptide synthesis. This method uses a rectangular block moved by a robot so that reagents can be pipetted by a robotic pipetting system. This block is separated into wells which the individual reactions take place. These compounds are later cleaved from the solid-phase of the well for further analysis. Another method is the closed reactor system which uses a completely closed off reaction vessel with a series of fixed connections to dispense. Though the produce fewer number of compounds than other methods, its main advantage is the control over the reagents and reaction conditions. Early closed reaction systems were developed for peptide synthesis which required variations in temperature and a diverse range of reagents. Some closed reactor system robots have a temperature range of 200°C and over 150 reagents.

Purification

Simulated distillation, a type of gas chromatography testing method used in the petroleum, can be automated via robotics. An older method used a system called ORCA (Optimized Robot for Chemical Analysis) was used for the analysis of petroleum samples by simulated distillation (SIMDIS). ORCA has allowed for shorter analysis times and has reduced maximum temperature needed to elute compounds. [30] One major advantage of automating purification is the scale at which separations can be done. [31] Using microprocessors, ion-exchange separation can be conducted on a nanoliter scale in a short period of time.

Robotics have been implemented in liquid-liquid extraction (LLE) to streamline the process of preparing biological samples using 96-well plates. [32] This is an alternative method to solid-phase extraction methods and protein precipitation, which has the advantage of being more reproducible and robotic assistance has made LLE comparable in speed to solid phase extraction. The robotics used for LLE can perform an entire extraction with quantities in the microliter scale and performing the extraction in as little as ten minutes.

Advantages and disadvantages

Advantages

One of the advantages to automation is faster processing, but it is not necessarily faster than a human operator. Repeatability and reproducibility are improved as automated systems as less likely to have variances in reagent quantities and less likely to have variances in reaction conditions. Typically productivity is increased since human constraints, such as time constraints, are no longer a factor. Efficiency is generally improved as robots can work continuously and reduce the amount of reagents used to perform a reaction. Also there is a reduction in material waste. Automation can also establish safer working environments since hazardous compounds do not have to be handled. Additionally automation allows staff to focus on other tasks that are not repetitive.

Disadvantages

Typically the cost of a single synthesis or sample assessment are expensive to set up and start up cost for automation can be expensive (but see above "Low-cost laboratory robotics"). Many techniques have not been developed for automation yet. Additionally there is difficulty automating instances where visual analysis, recognition, or comparison is required such as color changes. This also leads to the analysis being limited by available sensory inputs. One potential disadvantage is an increases job shortages as automation may replace staff members who do tasks easily replicated by a robot. Some systems require the use of programming languages such as C++ or Visual Basic to run more complicated tasks. [33]

See also

Related Research Articles

Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number of compounds in a single process. These compound libraries can be made as mixtures, sets of individual compounds or chemical structures generated by computer software. Combinatorial chemistry can be used for the synthesis of small molecules and for peptides.

<span class="mw-page-title-main">ELISA</span> Method to detect an antigen using an antibody and enzyme

The enzyme-linked immunosorbent assay (ELISA) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay is a solid-phase type of enzyme immunoassay (EIA) to detect the presence of a ligand in a liquid sample using antibodies directed against the ligand to be measured. ELISA has been used as a diagnostic tool in medicine, plant pathology, and biotechnology, as well as a quality control check in various industries.

<span class="mw-page-title-main">Digital microfluidics</span>

Digital microfluidics (DMF) is a platform for lab-on-a-chip systems that is based upon the manipulation of microdroplets. Droplets are dispensed, moved, stored, mixed, reacted, or analyzed on a platform with a set of insulated electrodes. Digital microfluidics can be used together with analytical analysis procedures such as mass spectrometry, colorimetry, electrochemical, and electrochemiluminescense.

<span class="mw-page-title-main">Automated analyser</span>

An automated analyser is a medical laboratory instrument designed to measure various substances and other characteristics in a number of biological samples quickly, with minimal human assistance. These measured properties of blood and other fluids may be useful in the diagnosis of disease.

<span class="mw-page-title-main">Microplate</span> Flat plate with multiple "wells" used as small test tubes

A microplate, also known as a microtiter plate, microwell plate or multiwell, is a flat plate with multiple "wells" used as small test tubes. The microplate has become a standard tool in analytical research and clinical diagnostic testing laboratories. A very common usage is in the enzyme-linked immunosorbent assay (ELISA), the basis of most modern medical diagnostic testing in humans and animals.

<span class="mw-page-title-main">Peptide synthesis</span> Production of peptides

In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl group of one amino acid to the amino group of another. Protecting group strategies are usually necessary to prevent undesirable side reactions with the various amino acid side chains. Chemical peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus (N-terminus). Protein biosynthesis in living organisms occurs in the opposite direction.

In chemistry, solid-phase synthesis is a method in which molecules are covalently bound on a solid support material and synthesised step-by-step in a single reaction vessel utilising selective protecting group chemistry. Benefits compared with normal synthesis in a liquid state include:

Dimethylformamide, DMF is an organic compound with the chemical formula HCON(CH3)2. Its structure is HC(=O)−N(−CH3)2. Commonly abbreviated as DMF, this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions. Dimethylformamide is odorless, but technical-grade or degraded samples often have a fishy smell due to impurity of dimethylamine. Dimethylamine degradation impurities can be removed by sparging samples with an inert gas such as argon or by sonicating the samples under reduced pressure. As its name indicates, it is structurally related to formamide, having two methyl groups in the place of the two hydrogens. DMF is a polar (hydrophilic) aprotic solvent with a high boiling point. It facilitates reactions that follow polar mechanisms, such as SN2 reactions.

Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds. Organic compounds are molecules consisting of combinations of covalently-linked hydrogen, carbon, oxygen, and nitrogen atoms. Within the general subject of organic synthesis, there are many different types of synthetic routes that can be completed including total synthesis, stereoselective synthesis, automated synthesis, and many more. Additionally, in understanding organic synthesis it is necessary to be familiar with the methodology, techniques, and applications of the subject.

<span class="mw-page-title-main">Thin-layer chromatography</span> Technique used to separate non-volatile mixtures

Thin-layer chromatography (TLC) is a chromatography technique that separates components in non-volatile mixtures.

The AutoAnalyzer is an automated analyzer using a flow technique called continuous flow analysis (CFA), or more correctly segmented flow analysis (SFA) first made by the Technicon Corporation. The instrument was invented in 1957 by Leonard Skeggs, PhD and commercialized by Jack Whitehead's Technicon Corporation. The first applications were for clinical analysis, but methods for industrial and environmental analysis soon followed. The design is based on segmenting a continuously flowing stream with air bubbles.

<span class="mw-page-title-main">Wet chemistry</span> Form of analytical chemistry

Wet chemistry is a form of analytical chemistry that uses classical methods such as observation to analyze materials. The term wet chemistry is used as most analytical work is done in the liquid phase. Wet chemistry is also known as bench chemistry, since many tests are performed at lab benches.

<span class="mw-page-title-main">Laboratory automation</span> Process improvement strategy for routine procedures

Laboratory automation is a multi-disciplinary strategy to research, develop, optimize and capitalize on technologies in the laboratory that enable new and improved processes. Laboratory automation professionals are academic, commercial and government researchers, scientists and engineers who conduct research and develop new technologies to increase productivity, elevate experimental data quality, reduce lab process cycle times, or enable experimentation that otherwise would be impossible.

In flow chemistry, also called reactor engineering, a chemical reaction is run in a continuously flowing stream rather than in batch production. In other words, pumps move fluid into a reactor, and where tubes join one another, the fluids contact one another. If these fluids are reactive, a reaction takes place. Flow chemistry is a well-established technique for use at a large scale when manufacturing large quantities of a given material. However, the term has only been coined recently for its application on a laboratory scale by chemists and describes small pilot plants, and lab-scale continuous plants. Often, microreactors are used.

Air-free techniques refer to a range of manipulations in the chemistry laboratory for the handling of compounds that are air-sensitive. These techniques prevent the compounds from reacting with components of air, usually water and oxygen; less commonly carbon dioxide and nitrogen. A common theme among these techniques is the use of a fine (100–10−3 Torr) or high (10−3–10−6 Torr) vacuum to remove air, and the use of an inert gas: preferably argon, but often nitrogen.

DNA-encoded chemical libraries (DECL) is a technology for the synthesis and screening on an unprecedented scale of collections of small molecule compounds. DECL is used in medicinal chemistry to bridge the fields of combinatorial chemistry and molecular biology. The aim of DECL technology is to accelerate the drug discovery process and in particular early phase discovery activities such as target validation and hit identification.

<span class="mw-page-title-main">Scavenger resin</span>

Scavenger resins are polymers (resins) with bound functional groups that react with specific by-products, impurities, or excess reagents produced in a reaction. Polymer-bound functional groups permit the use of many different scavengers, as the functional groups are confined within a resin or are simply bound to the solid support of a bead. Simply, the functional groups of one scavenger will react minimally with the functional groups of another.

<span class="mw-page-title-main">Automated synthesis</span> Type of chemical synthesis

Automated synthesis or automatic synthesis is a set of techniques that use robotic equipment to perform chemical synthesis in an automated way. Automating processes allows for higher efficiency and product quality although automation technology can be cost-prohibitive and there are concerns regarding overdependence and job displacement. Chemical processes were automated throughout the 19th and 20th centuries, with major developments happening in the previous thirty years, as technology advanced. Tasks that are performed may include: synthesis in variety of different conditions, sample preparation, purification, and extractions. Applications of automated synthesis are found on research and industrial scales in a wide variety of fields including polymers, personal care, and radiosynthesis.

<span class="mw-page-title-main">Autosampler</span> Device periodically collecting samples for an analytical instrument

An autosampler is commonly a device that is coupled to an analytical instrument providing samples periodically for analysis. An autosampler can also be understood as a device that collects samples periodically from a large sample source, like the atmosphere or a lake, for example.

The split and pool (split-mix) synthesis is a method in combinatorial chemistry that can be used to prepare combinatorial compound libraries. It is a stepwise, highly efficient process realized in repeated cycles. The procedure makes it possible to prepare millions or even trillions of compounds as mixtures that can be used in drug research.

References

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