Enzymatic Biosensors are Detecting Analytes with a Higher Specificity Than Before

A biosensor is a device that can detect a certain analyte or substance with high specificity. Examples of analytes are lactate, glucose, lactate, glutamate, and glutamine. Most of the biosensors can measure the concentration of an analyte in an aqueous solution, typically generating an electric signal. This signal is proportional to the concentration of the analyte in its measuring range.

General structure of a biosensor. Sensors by IST AG use enzymes to detect glucose, lactate, glutamine and glutamate. The transducer principle is electrochemical, producing a current as output signal (amperometric).

General structure of a biosensor. Sensors by IST AG use enzymes to detect glucose, lactate, glutamine and glutamate. The transducer principle is electrochemical, producing a current as output signal (amperometric).

An enzymatic biosensor consists of an enzyme to recognize and react with the target analyte, producing a chemical signal, a transducer to convert the chemical signal into a physical signal, and an electronic amplifier to condition and amplify the signal.

Analysis of complex biological media is enabled by biosensors. Detecting a large number of compounds is very important for process control in the food and chemical industry as well as for scientific research. In addition, it is invaluable in the health care sector for the diagnosis and treatment of diseases and to monitor illnesses. Continuous analysis of biological media is required in the biotechnological and pharmaceutical industries.

Such analyses are performed using analytical instruments like HPLC systems. While these systems are robust and reliable, they have limited suitability for online operations and are expensive. It is due to this reason that the acquisition of Jobst Technologies GmbH places IST AG as the main provider of reliable and high-performance online biosensors.

Enzymatic Biosensors for Metabolic Parameters

Clark and Lyons had launched the first glucose sensor in the early 1960s that uses an enzyme (glucose oxidase, GOx) as receptor and which is specific for glucose. Even in complex mixtures like fermentation broth and blood, enzymes allow the highly specific measurements of their corresponding analyte. It is similar to finding a needle in a haystack.

Analytes such as lactate, glutamate, glucose, and glutamine play a vital role in the metabolism of living organisms. Cell function and growth is supported by glucose and glutamine; cells produce lactate, which enables judging the efficiency of metabolism of cells; and glutamate is an amino acid consumed by cells. A specific set of enzymes is required to detect each of these analytes.

The continuous (on-line) monitoring of the concentration of such parameters allows the following processes among many others:

  • On-site analysis of food processes
  • The generation, optimization, and regulation of feeding strategies in cell cultures
  • The minimization of patients’ risks during surgery and intensive care

Versatile Sensors

Jobst Technologies GmbH has years of experience in enzymatic biosensors. Enzymes are immobilized in a stack of four permeable polymeric membranes on top of platinum micro-electrodes, which pick up electrical currents that occurs from the enzymatic reaction. Jobst Technologies; advanced membrane technology enables easy tuning of performance parameters like measurement range, response time, and sensitivity. This technology is also compatible with sterilization by irradiation (gamma, beta). These advantages make IST AG’s biosensors perfect for a wide range of applications.

Due to the small electrode sizes, a single chip can hold several electrodes at a time. Jobst Technologies offers the array sensor LV5 that consists of up to 6 sensitive electrodes where lactate, glucose, glutamate, and glutamine can be detected at the same time. It is also possible to analyze very small sample amounts of liquid as they flow through the 1-µL flow cell of the LV5. This makes the LV5 array sensor suitable for both online operation and offline analysis.

Cross-section of a flow-through LV5 biosensor featuring a flow-through cell for measuring of glucose, lactate, glutamine and glutamate

Cross-section of a flow-through LV5 biosensor featuring a flow-through cell for measuring of glucose, lactate, glutamine and glutamate

It is also worth mentioning that each sensor is factory-calibrated and marked in an automated process, which provides full traceability and makes it ideally suited for single-use and ready-to-use applications.

Biomedical Application - A New Landmark Product: EIRUS

Continuous surveillance of the blood values of critically-ill patients is important for optimal treatment. Maquet Critical Care, a leading company that provides medical systems for hospitals, has been setting a new benchmark by launching the EIRUS platform that is particularly developed to provide continuous monitoring of both lactate and glucose in critically-ill patients. Apart from optimizing patient care quality, it also reduces nurses’ workload compared to frequent intermittent blood analysis. The EIRUS system depends on a micro-dialysis technology that feeds a low-through sensor. Jobst Technologies GmbH has developed and manufactured this low-through sensor in Freiburg (Germany).

During a few days of continuous operation, the EIRUS system reports lactate and glucose blood levels every single minute and triggers alerts whenever the values fall beyond the preset ranges. This makes it easy to quickly assess the patient’s glycemic condition and ensures prompt and fast glucose management with insulin. Tighter glycemic control has been shown to benefit diabetic patients and also improve non-diabetic critical care patients who often exhibit a condition known as “stress diabetes”.

Elevated lactate levels or hyperlactatemia indicates increased morbidity and mortality. Monitoring of lactate levels allows for an early and continuous risk assessment, diagnosis, and therapy which reduce patients’ risks.

EIRUS system by Maquet for continuous monitoring of glucose and lactate in intensive care patients. Copyright: Maquet Critical Care

EIRUS system by Maquet for continuous monitoring of glucose and lactate in intensive care patients. Copyright: Maquet Critical Care

Biosensors - Their Application in Biotechnology

Cell cultures have recently started to help in the development of new drugs and medications. Animal cells are engineered to express antibodies and proteins that are used for treating a number of illnesses and conditions. To improve yield and product quality, the condition of cell cultures must satisfy optimal values. Monitoring of glucose and other nutrients is a critical factor in the feeding strategy of a cell culture. In biotechnology, one kind of glucose sensor is used that requires a fluidic-dilution stage but this needs to be outside the culture vessel. However, such systems develop problems like large latency owing to the transit time through the dilution stage, contamination risks as it is essential to invasively take samples within the bioreactor, more footprint since an external analyssis is needed, and dealing with the dead volume in the tubes. Other types of sensors cannot survive prolonged shelf storage following sterilization by irradiation. IST AG and Jobst Technologies developed a technology that enables continuous glucose monitoring either inside the culturing vessel or using a probing system.

A Chinese-hamster-ovary (CHO) cell line was used for a batch1 culture in a traditional glass bioreactor, and the concentration of glucose was continuously monitored for a number of days. A Nova Bioprofile Analyzer and a HPLC system were used for the control measurements. The sensors were gamma-irradiated and stored prior to utilization, due to their robustness. Although sensors are pre-calibrated, a single calibration at start delivers enhanced accuracy across the entire cultivation lasting days. During this time, a measurement point is obtained every second without needing any manual work as the used reference systems do.

Comparison of glucose values during batch culture

Comparison of glucose values during batch culture

Acknowledgements

Special thanks to Dr. Caspar Demuth, Dr. Iris Poggendorf, Fabienne Seiler and Irène Stutz from the Zurich University of Applied Sciences (Institute for Biotechnology, Wädenswil, Switzerland) for carrying out the cultivation and providing us with the data.

1 In a batch culture, the nutrient medium has starting glucose concentration and no further nutrient feeding is performed.

This information has been sourced, reviewed and adapted from materials provided by Innovative Sensor Technology, USA Division.

For more information on this source, please visit Innovative Sensor Technology, USA Division.

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