How will a tumor react to different medicines? What impact do contaminants have on water plants? There are many situations when it’s essential for medical experts and biologists to know precisely how cells and tissues will react. Only then can they decide what to do next. Scientists at the Heinz Nixdorf Chair for Medical Electronics at the TUM in Munich have spent years designing microsensor chips and entire sensor systems that can help them do exactly that: evaluate and monitor the behavior of cells and tissues. Drawing on this technology, researchers at the Steinbeis Transfer Center for Cell Chip Technologies have been working with business partners to develop analytical devices for a broad variety of applications, and these have already made their way into products supplied by small and medium-sized enterprises (SMEs).
Cells have so much to tell us but they can’t talk. Living cells react constantly to influences in the environment, and, when they do, they communicate with their surroundings. For example, they react to chemical and physical stimuli by adapting their metabolic activity. This can be seen when oxygen is released or used, or when the pH value of their direct surroundings goes up or down. But they could also react by producing proteins, increasing the rate of cell division, or even by dying off. Under the directorship of Prof. Dr. Bernhard Wolf, the experts at the Heinz Nixdorf Chair for Medical Electronics in Munich have developed multi-parametric microsensor chips capable of capturing lots of these reactions. These bio-hybrid sensors cultivate cells directly on the surface of the sensor. “The cells practically grow with the sensor, so it can then precisely measure exactly what the cells are actually doing and if they’re alive,” explains Bernhard Wolf, who also manages the Steinbeis Transfer Center for Cell Chip Technologies.
But that was just the first step. Next, the scientists developed the biohybrid sensors into lab-on-chip systems. With these, reagents are placed in a reaction chamber located on the biosensor. This makes it possible to precisely examine things like how cells react to certain substances. Lots of animal testing might be avoided by this method because the chip practically replaces live laboratory animals. For example, oncologists can test the influence of cytostatic agents on tumor cells.
To make their systems available for mobile applications outside clean room environments, the Munich-based researchers worked with a company called Cellasys to develop an “intelligent mobile laboratory for in-vitro diagnostics,” or IMOLA-IVD. At the heart of their systems lies a bio-hybrid chip with sensors for detecting pH values, oxygen, impedance, and temperatures. There is a reaction chamber on top of this. The systems include tubes and a pump to add substances and nutrient solutions for the cells. This is fully automatic. It is possible to link up several of these individual, enclosed systems and run them in parallel. This increases the throughput rate of experiments (e.g., 6-fold IMOLA-IVD). There is a software module to control the sequence of experiments, gathering, processing and interpreting the different measurements. In the future, it will be possible to use the IMOLA system for individual courses of chemotherapy, the development of active ingredients in regenerative medicine, and as an alternative to animal testing.
Bio-hybrid chips also have uses in food and drinks monitoring as well as in environmental applications. The scientists have now miniaturized their system and come up with a portable, wireless handheld device called the μLa (=micro-lab). “You can take measurements with bio-hybrid construction elements, completely independently of laboratory equipment and electricity,” explains Bernhard Wolf. “So you can even do it outdoors or collect samples in warehouses or grocery stores.” For example, thanks to yeast cells growing on the integrated biochip, the handy device can be used to measure fungicide on fruit. It can be seen if they’re alive by adding a sample of the food (and, if present, also the contaminant). The μLa displays the results on a screen although it can also send them to a database through the cell phone network. These can then be collated and interpreted. Testing carried out until now has shown that living cells are indeed a sensitive “signal convertor” for food testing. “With the microlab, tests can be carried out really quickly and accurately on xenogenic residues,” says Wolf.
Of course there are also times when it’s not about being mobile and more about high volumes. When looking for active substances or carrying out tumor therapy the priority is to provide large batteries of measurements within a short timescale. One results of the collaborative project at the Steinbeis Transfer Center for Cell Chip Technologies is a fully automatic analysis system called the Intelligent Microplate Reader (IMR). To make this, the scientists position their biosensors on the surface of a microtiter plate, placing a multiparametric sensor in each of the 24 wells on the plate. It’s on this plate that the cells grow (for example tumor tissues from a patient). Thanks to an ingenious flow system, the systems can be provided with plenty of fresh nutrient solution. The IMR also has a fully automated pipette robot which can inject different substances in the 24 wells in a single sweep, or even 24 different concentrations of the same substance. This allows the machine to quickly pinpoint which chemotherapeutic agent a specific patient’s tumor cells react best to, and in what dosage – or which mixture of active substances works best. This makes it possible to define treatment that matches perfectly with the specific patient – more effectively and yet still more gently/carefully than conventional cancer treatment.
This method requires a biopsy to remove tumor tissue from the patient and place this on the sensors. Alternatively, there is the option of implanting sensors in the patient. Such intelligent implants can monitor tumors and, in the future, they may even help cure them. They are no bigger than a sugar cube in size and on the inside they contain a button cell battery and a radio unit. Such active implants can be implanted in the body near tumors in situations where it would be difficult to operate. The sensors are positioned on the outside of the implants to measure oxygenation in the tissue and send data to a receiver outside the body. This makes it possible to work out the growth rate of the tumor. If the tumor grows, the doctor can react accordingly.
“Our goal is to develop a closed-loop system,” explains Wolf, referring to the latest research projects. If the implant spots tumor growth, it could inject a chemotherapeutic agent directly into the tumor from an integrated substance reservoir. This would be an effective and comparably gentle procedure for the patient. As the professor underscores, “that would make it possible to avoid the heavy strain placed on the liver and kidneys by aggressive medication when it’s injected intravenously.” In the future, similar implants could even be used to monitor bone healing or be used in orthopedic implants. They could also help care for wounds or be used with transplants. This is because, in such cases, it is also important to assess tissue oxygenation to understand the condition of certain parts of the body.
The Munich-based researchers have also come up with a particularly clever way to print sensors onto plastic foils using an inkjet printer. They call these nanoparticle sensors and they are inexpensive and effective. Because the foils are so delicate, they can be rolled up into small capsules that can be swallowed. Inside the capsules, there are microelectronic chips, a battery and a radio unit – all in a miniature format. The sensors on the outside of the foil could then identify a bleeding stomach ulcer and attach themselves to it. The “intelligent nano-pill” could then monitor the ulcer, transmit data to the outside and maybe even administer medication – precisely in the right place next to the ulcer, without causing the patient unnecessary discomfort. The sensor pill is already under development and it could soon be ready for first trials.
Christian Scholze works at the Heinz Nixdorf Chair for Medical Electronics at the TUM in Munich. Prof. Dr. Bernhard Wolf is director of the Steinbeis Transfer Center for Cell Chip Technologies which was founded at the TUM in 2000. The center is closely involved in the field of biomedical sensors, actuators used in diagnostics, and medical treatment, bioelectronics test systems used in environmental analysis, microsensor array technology, the biophysical characterization of cellular systems, and analytical electron microscopy.
Prof. Dr. Bernhard Wolf
Steinbeis Transfer Center Cell Chip Technologies (Munich)
su0564@stw.de
Christian Scholze
Heinz Nixdorf Chair for Medical Electronics at TUM Munich