Diagnostics and Sensors

Label-free detection methods - i.e. without additional reagents for molecular characterisation - have a high development potential as they can provide simpler diagnostic tools that can be used outside the laboratory and thus become accessible to non-specialist users. Fraunhofer IPMS is developing photonic label-free biosensors based on silicon nitride microring resonators in silicon technology. They are used for the selective detection of biomarkers or microbial substances and offer, for example, a suitable detection method for the early detection of diseases. 

For this purpose, Fraunhofer IPMS and Fraunhofer IZI are developing a highly sensitive integrated photonic biosensor platform.

Deep vein thrombosis (DVT) and its fatal complication pulmonary embolism afflict millions of people worldwide and are responsible for a large percentage of acute hospitalizations. Deep vein thrombosis (DVT) is the formation of a blood clot within the deep veins, most commonly those of the lower limbs, causing obstruction of blood flow. In 50% of people with DVT, the clot is at some point detached from the vein wall and travels to the lung to cause pulmonary embolism. About 25% of people experiencing pulmonary embolism will die from it, making it the 3 leading cause of cardiovascular death worldwide after stroke and heart attack. Clinical assessment of DVT is notoriously unreliable because up to 2/3 of DVT episodes are clinically silent and patients are symptom free even when pulmonary embolism has developed.

Early diagnosis of DVT is crucial and has been proven to prevent life-threatening complications (pulmonary embolism), minimize the risk of long-term disability (post-thrombotic syndrome, recurrent DVT), improve treatment outcomes, and reduce healthcare costs. ThrombUS+ brings together an interdisciplinary team of industrial, technology, social science and clinical trial experts to develop a novel wearable device for continuous, operator free continuous monitoring in patients with high DVT risk.

Fraunhofer IPMS is developing the ultrasound transducer array for wearable, point of care DVT continuous monitoring together with VERMON. We are focusing on our CMUTs (Capacitive Micromachined Ultrasonic Transducers), which are MEMS-based transducers considered the next generation of medical ultrasound devices. CMUTs can be manufactured at low cost due to high-volume production. Additionally, advantages like miniaturization with high channel numbers, high bandwidth in combination with high sensitivity will help to develop a completely new device. 

In cases of infection of the middle ear, particularly among infants and young children, antibiotics are often the remedy of choice. Yet the equipment used to diagnose this condition has stood still for a number of decades. As a result, doctors can only deliver a diagnosis that is subjective and unreliable. On average, diagnostic accuracy for this condition is as low as 50 percent, not least when it comes to distinguishing between a bacterial and viral infection. This means that lots of children are prescribed antibiotics unnecessarily. This, in turn, is feeding a growing resistance to antibiotics worldwide. 

However, a new type of ultrasound transducer developed at Fraunhofer IPMS can resolve this dilemma. It employs air-coupled ultrasound to enable a precise diagnosis of infection of the middle ear. Pediatricians and other doctors can use an otoscope to examine the external auditory canal and, more particularly, the area behind the ear drum. In a matter of seconds, they are able to tell whether there is air or fluid in the middle ear, and to characterize this fluid. This will permit them to distinguish between different stages of the illness and thereby determine the appropriate treatment.

The ultrasound transducer is a so called CMUT (capacitive micromachined ultrasonic transducer). It is produced on a silicon wafer by means of special microelectromechanical systems (MEMS) technology developed at Fraunhofer IPMS. The transducer has a low power consumption and can be mass-produced cheaply. And, unlike traditional ceramic piezoelectric ultrasound transducers, the MEMS transducer can be miniaturized. This is a major advantage, because it means the CMUT can be incorporated much more easily in an otoscope.

The Corona pandemic poses a challenge for medical diagnostics: In addition to severe symptoms, the SARS-CoV-2 virus also causes mild symptoms that can worsen very quickly. However, continuous patient monitoring has so far only been available in intensive care units. As a result, sudden deterioration in health is often only recognised with a time delay and those affected are brought to hospital too late. This is exactly where the cluster project M3Infekt comes in. By mobile recording, analysis and fusion of relevant biosignals with the help of different technologies, valid diagnoses can be made about the condition and course of the disease.

In the long term, the system under development will address decentralised patient monitoring on normal wards and in non-clinical environments using multimodal parameters of the cardiovascular system (including heart rate, ECG, oxygen saturation, blood flow situation) and respiration (including respiratory rate/volume, respiratory air analysis). Machine learning methods will be used as the basis for evaluation, which facilitates diagnostics and ensures that the system can be easily integrated and deployed in various application scenarios.

Diseases can be detected by analysing the air we breathe. For example, traces of specific gases in the breath are an early sign of various diseases, including cancer. Spectroscopic breath analysis can detect these gases and thus enable early diagnosis and thus prompt therapy. Corresponding chemical sensor systems that can be used in everyday life are based on a MEMS ion mobility spectrometer, which can be used to provide procedures for rapid tests.

Lab-on-chip (LOC) diagnostics is now the state of the art in various laboratory diagnostic procedures. It enables the automated processing and evaluation of samples. Diagnostic results can thus be provided faster, earlier, and more cost-effectively than with conventional analysis in a medical laboratory. However, lab-on-chip systems are not available for all applications. Together with partners, the Fraunhofer IPMS is therefore developing new components and modules for LOC diagnostics in cytokine release syndrome.

Cytokine release syndrome (CRS) can occur with various diseases and therapies (e.g., immunotherapy, sepsis, and infectious diseases such as COVID-19). In a CRS, cytokines are produced as part of the body’s immune response, thereby activating more immune cells. These migrate to the site of inflammation and produce cytokines that trigger an excessive immune response. This does not subside automatically – as is usually the case – but rather continues to intensify. Because this serious side effect can be fatal, it must be diagnosed and treated as soon as possible.

Cell-based therapies are usually personalized to the patient and are often still very expensive due to the sometimes very complex manufacturing processes. For people with a critical stage of the disease, timely production is often vital. As part of MIC-PreCell, modern methods of integrated quality assurance will therefore be established, with which the manufacturing processes can be shortened and any production errors can be detected considerably earlier.

The project team is focusing on the broad use of innovative quality assurance methods in cell production, such as optomechanical profiling, which can be used to determine mechanical cell properties immediately and without marking. The Fraunhofer researchers also want to use a gas chromatograph-ion mobility spectrometer to analyze VOCs, volatile organic compounds, which are released into the outside air by cell cultures. In addition, devices for the micromanipulation of cells and cell clusters or organoids will be used to provide direct and detailed real-time information on the condition of therapeutic cell products.

Data glasses could open up a whole new quality of treatment for doctors. For example, they could have X-ray images or real-time images from endoscopes directly in their field of vision during treatment without having to look away from the operating field. Hands can remain free.

These functions often require ultra-high resolution, flexible substrates, sunlight readability, high contrast, gesture and eye control, scratch resistance and others. It is precisely these types of microdisplays that are being developed at Fraunhofer IPMS.

The growing market for wearables also requires special miniaturized solutions with low power consumption. New device functions are in demand here. Innovative input and interaction concepts, such as bidirectional microdisplays (combination of display and imager on one chip), also make it possible to control content via eye movements.

A sensor for measuring the oxygen concentration in gases using a specially developed sensor layer or commercial sensor spots. A blue OLED excites the dye layer and the response phosphorescence signal is detected and evaluated in the CMOS backplane chip. Using a calibration curve, the oxygen concentration is calculated from the decay time of the dye response.

Medical applications for micro scanners include image acquisition for medical endoscopes, confocal microscopy, fluorescence microscopy, spectroscopy and ophthalmology. A few years ago, for example, Fraunhofer IPMS developed double-resonant MEMS scanners that form the core of a compact X-ray film scanner for digitalized dentistry.

Other applications of Fraunhofer IPMS medical technology include the laser scanner development for the company Norlase that are used in ophthalmology to treat retinal and glaucoma patients. The use of MEMS scanners from the Fraunhofer IPMS makes it possible to achieve an unprecedented miniaturization of the system and a higher resolution.

For the start-up company Envision Diagnostics, the institute is developing micro scanners for a standardized, fast and reliable eye test that records, evaluates and displays all qualitative parameters. This will provide doctors with more comprehensive and reliable patient data, enabling them to make safer decisions. 

The Eurostar project UltraLASE is developing the highly portable LYNX Ophthalmokop with pattern scanning, which enables multi-spot laser treatment of eye diseases such as diabetic retinopathy. This offers advantages over single-spot systems, such as better patient tolerance, shorter treatment times and higher patient throughput. This development is particularly important in view of the growing global demand and increasing undersupply in ophthalmology, especially due to the ageing society and diabetes.

The LYNX system is being developed by the Danish company Norlase, and no comparable system currently exists. For the first time, it enables efficient laser treatment for previously untreated patient groups, such as bedridden patients, newborns and medical missions.

A key factor in the project is the ultra-miniaturized scan module, which is based on a 2D MEMS scanner mirror. This module will scan an area of 8° x 8° with a 519 nm laser and deliver an average laser power of 1.5 W. The challenge lies in minimizing the module volume to max. 4 cm³ with a positioning time of max. 3 ms. The developed module will be integrated as a core component in the LYNX laser coagulation system from Norlase and thus contribute to the further development of ophthalmology.