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Advancing Human Health Through Microelectronics

By IMMS | 11.13.17

IMMS presents microelectronic solutions to cancer diagnosis, blindness at Medica 2017.

At Medica 2017 in Düsseldorf, Germany, IMMS is presenting three microelectronic health solutions: a mobile testing system for early cancer diagnosis, microelectronics for the analysis of aqueous solutions with the help of passive RFID sensors, and a Bionic Vision System to compensate for blindness. Functional models and prototypes illustrate the current state of research and development activities on bioanalysis carried out at IMMS Institut Für Mikroelektronik Und Mechatronik-Systeme). Furthermore, the Institute is introducing a chip development for medical technology which is part of Pixium Vision’s IRIS II epi-retinal system presently being investigated in clinical studies.
 
Functional Model for Quantitative Point-of-Care Cancer Diagnosis
 
There are certain types of cancer for which the patient’s doctor can test rapidly on the spot, obtaining an immediate result and thus resulting in saving costs and time-consuming lab tests. Present rapid tests are no more than qualitative and produce results confined to "yes" or "no." For colon and prostate cancer to be diagnosed at a very early stage, IMMS is developing microelectronics coming into direct contact with a sample and being capable of recognising concentrations of antigens in the range of one nanogram per cubic centimetre. Via live-demo of the functional model, IMMS is presenting the detection principle for which the current work is based.
 
Via live-demo of a functional model, IMMS illustrates the detection principle which is carried out in the INSPECT project with four partners in Thüringen, Germany. It is the role of IMMS to develop the application-specific microelectronics, focusing on signal processing, particularly in the case of very weak signals, and efficient noise suppression for these. The chips are currently being used by the Senova Gesellschaft für Biowissenschaft und Technik mbH to conduct extensive test series with biological samples. The foundation is Senova’s expertise in immunological assays and in biochemical surface functionalisation of chips. Thanks to the combination of immunological testing methods with microelectronics it becomes possible to precisely and reliably verify at an early stage the lowest concentrations of cancer biomarkers.

If it were possible to measure the exact concentration of certain molecules in sample fluids, reliable diagnosis could be achieved. Particularly in the case of cancer of the prostate, there would be a great improvement if the on-site diagnostics could include such quantitative analysis. Although the presence of PSA (prostate-specific antigen) may be an indicator of cancer, it is constantly being produced in the male body. A man less than 50 years old will have a PSA concentration of less than 2.5 ng/ml (the unit is in thousand-millionths of a gram, i.e. in nanograms, per millilitre). Men over 70 will usually have a level around 6.5 ng/ml. It is possible for these values to vary independently of age; the cause may be inflammation, mechanical irritation or cancer. If there is a carcinoma developing, the patient’s PSA concentration will be rising continuously. If the PSA concentration could be measured at regular intervals, reliable early diagnosis and early treatment would result.

The biotechnical principles on which the new test system will be based are comparable with those for the strip test. The interaction between antibody and antigen is intended to enable detection of analytes in a sample: PSA in the case of prostate cancer and haemoglobin in the case of colon cancer. To meet the diagnostic needs, the chip must be capable of recognising concentrations of antigens in the range of one nanogram per cubic centimetre. These low concentrations induce very weak fluctuations in the luminous intensity, between 0.01 Bel and 1 Bel.

IMMS has thoroughly investigated the technical feasibility of achieving this level of accuracy for the purpose of cancer diagnosis. As a first step an already available chip originally intended for detecting infectious diseases was evaluated to see how it would visualise varying levels of brightness in sample fluids where the concentration of particles is known. TMB (tetramethylbenzidine) substrate solutions were deposited on this chip and the TMBs were enriched with HRP (the horseradish peroxidase enzyme). The chemical reactions which took place turned the fluids blue—the lower the concentration, the more slowly. The chips were used to measure the gradual attenuation of light due to staining over time and tiniest HRP quantities have already been verified.

For this purpose, four sample solutions were used which contained 0 ng/ml, 0.2 ng/ml, 1 ng/ml and 5 ng/ml of HRP respectively. For each sample, on addition of the specified HRP concentration, a brightness value was recorded for each second over a period of 600 seconds. These recordings proved that the alterations in brightness were indeed in the range 0.01 Bel to 1 Bel and the visualized differences in the reaction processes were consonant with expectations. It is intended to rely on this preparatory work in developing correlations for the analyte concentrations which would prove the presence of PSA and haemoglobin to specify requirements for the new chip design.
 
A Passive RFID Sensor Prototype for the Analysis of Aqueous Solutions
IMMS is also demonstrating a passive RFID microelectronic chip with remote power supply. Placed into aqueous solutions, the chip measures temperature data which is captured and processed by an RFID reader unit. With this energy-efficient chip developed by IMMS, values are being measured and digitized with a power consumption of very few microwatts (approximately 3.5 microwatt). This would facilitate the use of a sensor operable without interruption for at least a 10-year period from a mignon battery with a typical capacity of 1000 mAh. Thanks to this ultra-low power consumption a battery is dispensable: an RFID reader unit generates an electromagnetic field which is sufficient to supply the passive RFID chip with power and to record and send data through containers and liquids over distance of up to four centimetres. The batteryless principle for RFID sensors being introduced at Medica is currently being transferred by IMMS to other measurands.
 
The development is a result of the ADMONT European Union joint project which sees IMMS doing research and development on the design of intelligent in-vitro diagnostic und bioanalytical sensor and actuator systems and which will run until 2019. The RFID-Chip combines high accuracy, energy-efficient operation and cost efficiency. The new digital RFID-coupled temperature sensor acquires values in the large measuring range from –40 degrees Celsius to 125  degrees Celsius with an accuracy of +/–0.5  degrees Celsius. To reach a power consumption of only 3.5 microwatt, IMMS eliminated analog-to-digital converters which consume much energy. As a substitute, IMMS implemented a time-coded signal processing which allows the conversion of temperature values into timing signals. This digital information can be handled with minimised energy consumption. For a low-cost solution IMMS harnessed off-the-shelf, reasonably priced CMOS technology and developed a single-chip solution with integrated sensors and with embedded electronic signal processing. This chip does not need any further components besides the RFID antenna.
 
IRIS II—Epi-Retinal System of Pixium Vision to Compensate for Blindness
IMMS has developed a biocompatible microelectronic chip as part of a retinal implant system with which people who have lost their sight from retinitis pigmentosa but with an intact optic nerve are learning to partially see again. A camera integrated into the spectacles records images of the environment which are transferred through the pupil to the retinal implant. There, the IMMS chip converts the optical information into an electronic data stream which is passed to the retina stimulator for the excitation of the optic nerve cells to elicit visual perception in the brain. The patients of the IRIS II European clinical trial are currently learning to interpret the new perception in their re-education program. IMMS is showcasing the system at Medica, as well as the devices with which those patients are being equipped and video examples from on the study with patients' experiences.
 
"Such a retinal implant is a big challenge from an engineering point of view, not only with regards to miniaturization and functionality," said Khalid Ishaque, CEO of Pixium Vision, looking back over 15 years of research and development. "Imagine wanting to have a working TV underwater in the Mediterranean Sea, which is warm, moving and salty. It’s kind of similar challenge for such a microelectronic implant in your eye." The electronic implant needs to be flexible and function while the eyeball is moving. In addition, it has to operate energy-efficiently and within harmless thermal safety thresholds. Furthermore, in the human body, power supply cannot be delivered with a direct current, usual for such circuits. So for the chip design a solution with alternating voltage had to be found.

The infrared receiver chip developed by IMMS is implanted into the inner eyeball and translates the incoming information from the optical interface into a current signal which is transferred to the stimulator chip. As essential elements for implementing this functionality IMMS created and tested the photodiode, the control circuit for signal detection and the output driver. For a minimum energy consumption, for a low heat generation and for a constant operational state IMMS has implemented circuit design concepts which only need a current consumption of less than 120 µA.
IMMS has developed an energy supply for the chip using alternating voltage, which is transformed by a rectifier into an internal direct current exclusively used in the hermetically sealed circuit. For this reason, the evaluation of the supply current could not be run using standard measurements. Therefore, IMMS has developed an especially adapted measuring method with which the value of the supply current is being identified with the use of an inductive current probe.

"IMMS delivered a vital contribution to our goal of restoring partial perception to people with vision loss from retinitis pigmentosa. The chip made by IMMS is the fundamental part of the gateway between the real world to the eye through the optic nerve and the brain of the patient," said Ishaque. “But for him, after surgery the hard work starts—which involves retraining the brain." For this huge challenge Pixium Vision has been cooperating with multi-disciplinary partners at the cutting edge of neuroscience, physics, optics and mathematics, microsurgery, ophthalmic surgery, and low vision experts. "This global ecosystem of partners is critical to the success on this journey, which was not so long ago considered impossible," Ishaque concluded.

Pixium Vision has also been authorized to start a clinical study in human for PRIMA, a sub-retinal miniaturized wireless implant system to treat advanced atrophic dry-AMD, the most prevalent form of age-related macular degeneration.
 
IMMS’ life science focus is the research and development of application-specific integrated electronic circuits (ASICs) and sensor systems for quantitative rapid tests and in-vitro diagnosis and for the monitoring of therapeutic progress. The systems bring closer a future of point-of-care testing for, among other things, early cancer diagnosis, which is fast, reliable, cheap and largely automated. IMMS therefore builds upon its multi-parameter microelectronics-based platforms and harnesses off-the-shelf, reasonably priced fabrication techniques and CMOS technology, incorporating them into diagnostic systems. One important research focus of IMMS is the integration of a variety of detection principles into a single electronic sensor chip which can be used to measure biological and chemical features. IMMS works in close conjunction with its life science partners to match the systems to their application, for instance by providing interfaces that are made of biocompatible materials or by accommodating the packaging.
 
IMMS works on solutions for harsh conditions and for high-precision applications. It develops energy-efficient, robust and biocompatible electronic sensor and actuator systems. Such systems are able, for example, to acquire, to process and to send data out of implants, fluids or humid environments over years. Furthermore, IMMS develops high-precision drives for use in medical technology and for a particle-free manufacture of biotech products with a precision less than one nanometre.
 
The ADMONT project has revived funding from the ECSEL Joint Undertaking. This Joint Undertaking has revived support as Innovation Action from the European Union's Horizon 2020 research and innovation programme, the German Federal Ministry of Education and Research (BMBF) and Finland, Sweden, Italy, Austria, Hungary.

IMMS is presenting its microelectronic solutions in Hall 3, Stand G60. Medica is taking place Nov. 13-16.