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Medicine and Health

Blood chemistry in real time

   
 
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The scientists and clinicians from four countries brought together in this project have devised a prototype instrument for continuous and rapid monitoring of the blood chemistry of patients in intensive care.
The instrument employs a microdialysis 'mini-shunt' to extract molecules of interest from the bloodstream, a miniaturised flow system to handle very small volumes of fluid, new biosensors to measure small amounts of glucose and lactate, and a computer system to process and display the results in real time.
Although the instrument has been successfully tested on animals, further development depends on the team finding a suitable industrial partner. Other applications could be found wherever rapid and continuous chemical monitoring is required.

Continuous monitoring of patients in intensive care is now routine. Vital signs such as heart rate, blood pressure, body temperature and urinary output may all be measured continuously using physical sensors, with the information immediately available to doctors. However, it is not yet possible to monitor the blood chemistry of a patient in a similar way.
That may change if a prototype monitoring system developed under the EU's Standards, Measurements and Testing Programme comes to fruition. Scientists and clinicians from Dublin, Berlin, Vienna and Basel have collaborated on a new method of continuously measuring the amounts of two important blood chemicals - glucose and lactate.

Two critical chemicals

Glucose, or blood sugar, is the means by which energy from food is made available within the body. Energy is released when the glucose combines with oxygen to produce carbon dioxide and water. Where the supply of oxygen is restricted, however, a chemical called lactate starts to accumulate in the blood.
A raised level of lactate is regarded as a sign that some part of the body is being deprived of oxygen, a condition known as tissue hypoxia. Continuous monitoring of lactate would give early warning of impending trouble, especially in cases of bacterial infection and shock, which are major causes of death in intensive care patients. Likewise, patients suffering from diabetes, who lack the means to control their blood sugar, would benefit from having their glucose levels monitored continuously when they are in diabetic coma and during surgery for other conditions.
Although much research has been carried out in this area, the system developed under this project is believed to be unique in being able to simultaneously monitor blood glucose and lactate rapidly and accurately, using several innovative technologies.

Biosensors and Microdialysis

At the heart of the instrument is a biosensor, a device that detects the presence of specific molecules by their interaction with an enzyme placed onto an electrode. As the enzyme breaks down the molecules a small electric current is produced - the greater the concentration of molecules, the greater the current.
By an appropriate choice of enzyme, biosensors can be made sensitive to a variety of molecules including, in this case, glucose or lactate. The biosensors used in this system were designed jointly by the research teams at the Max Delbrück Centre for Molecular Medicine in Berlin and the Technical University of Vienna.
However, human blood is a rich cocktail of many complex molecules, and the sensors would be contaminated if they were directly exposed to it. Accordingly, researchers at St Vincent's Hospital in Dublin employed a technique known as microdialysis to take a sample of glucose and lactate from the blood.
A catheter, inserted into the patient's central vein, often already in place for other purposes in intensive-care patients, diverts a small flow of blood around a circuit and back to the body. In one section of the circuit the blood flows through a 'mini-shunt'. This consists of an outer tube, in which the blood flows, surrounding a thin hollow fibre containing a fluid flowing in the opposite direction. The fibre is porous to small molecules such as glucose and lactate but holds back large molecules such as proteins. As the blood flows over the fibre, glucose and lactate molecules pass through into the collecting fluid inside.
Rates of fluid flow through the fibre, however, are extremely slow, about 3 microlitres per minute. The instrumentation required to handle this fluid must be correspondingly small if the system is to produce measurements quickly.

Microflow technology

The answer, devised at the CIBA laboratories in Basel, was to use a 'microflow stack' of 22-mm square silicon wafers, looking somewhat like a squat office block. The sample fluid comes in at the top of the stack and then trickles down through holes and channels etched into the wafers until it reaches the biosensors in the 'basement'.
It then passes back up through the stack and is finally collected for disposal. The stack allows calibration solutions to be directed to the sensors and also permits other chemicals to be mixed with the sample fluid where required.
The sensors themselves, and the fluid cell containing them, are formed directly on to a printed circuit board by thin-film technology. Channels in the board conduct the fluid from the base of the stack to the cell. In future versions of the instrument the sample fluid could then be passed to a number of other sensors for further measurements to be made. The combined flow volume of the stack and cell is only 8 microlitres.
The entire system is controlled by a laptop computer running software designed at Dublin City University. The package has two main components: a microdialysis control program which controls the rates of flow, valve settings, system calibration, data acquisition and processing; and a viewing program for inspecting and displaying data. Graphical and numerical displays are presented to the user in a Windows-based virtual instrument panel.

Promising results

Although the prototype has not yet been tried out on human patients, tests on anaesthetised dogs have been promising. Continuous measurements of glucose and lactate compared well with those made by intermittent blood sampling and measurement using conventional instruments. The system is sensitive to normal blood levels of the chemicals as well as the raised levels found during illness. Because of the low volume of fluid in the system, changes of glucose and lactate in the body can be detected and displayed within five minutes of their occurrence.
However, there are a number of problems to be solved before the prototype can be transformed into a marketable instrument. Some of these are technical, such as further miniaturisation, long-term stability, and the prevention of blood clotting in the mini-shunt.
But the greatest problem, now that the research project has been completed, is the need for further funding. Medical devices have to meet strict European safety standards and the development work to ensure safety and quality assurance can be very expensive. The participants hope to find an industrial partner willing to provide the necessary backing to see the project through to completion.
Further applications are possible wherever rapid and continuous chemical monitoring is required, such as in the biotechnology industry, industrial process control and environmental monitoring.

 

Project Title:  
Novel instrumentation for real-time monitoring using miniaturised flow systems with integrated biosensors

Programmes:
Industrial and Materials Technologies (BRITE-EURAM/CRAFT/SMT)

Contract Reference: MAT1-CT93-0009

Cordis DatabaseFor more information on this project,
go to the CORDIS Database Record

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