Mario Birkholz

IHP | Institute for High Performance Microelectronics · Joint Lab Bioelectronics

The progressive scaling in semiconductor technology allows for advanced miniaturization of intelligent systems like implantable biosensors for low-molecular weight analytes. A most relevant application would be the monitoring of glucose in diabetic patients, since no commercial solution is available yet for the continuous and drift-free monitoring...

The geometrical shape of ions in crystals and the concept of ionic radii are re-considered. The re-investigation is motivated by the fact that a spherical modelling is justified for p valence shell ions on cubic lattice sites only. For the majority of point groups, however, the ionic radius must be assumed to be an anisotropic quantity. An appropri...

The application of Raman spectroscopy as a monitoring technique for bioprocesses is severely limited by a large background signal originating from fluorescing compounds in the culture media. Here we compare time‐gated Raman (TG‐Raman)‐, continuous wave NIR‐process Raman (NIR‐Raman) and continuous wave micro‐Raman (micro‐Raman) approaches in combina...

Microalgae constitute an abundant source of poly-unsaturated fatty acids which are applied in various biotechnological fields such as pharmaceuticals and food supplement. Separating microalgae cells with respect to their lipid content would establish a relevant at-line analytical technique. The present study demonstrates an electrical approach for...

The file contains the presentation slides shown in an oral contribution to the "4th European Biosensor Symposium" taking place in Aachen, August 2023.

The sector of information and communication technology (ICT) has seen a steady increase in global energy consumption, accounting for 5-8% of global electricity consumption in 2020 and for 3% of all greenhouse gas emissions [1]. In particular, the evolving Internet-of-Things (IoT) will become a major consumer with a projected increase from 15e9 devi...

Nucleoside analogues are important compounds for the treatment of viral infections or cancers. While (chemo-)enzymatic synthesis is a valuable alternative to traditional chemical methods, the feasibility of such processes is lowered by the high production cost of the biocatalyst. As continuous enzyme membrane reactors (EMR) allow the use of biocata...

Implantable microelectronic systems offer new and innovative approaches for medical diagnostics and therapy. Functional implants for the treatment of cardiovascular diseases acted as pioneer systems and have undergone decades of development. The experience gained has found its way into other medical implants such as orthopedic prostheses or neuroph...

The performance of receptor-based biosensors is often limited by either diffusion of the analyte causing unreasonable long assay times or a lack of specificity limiting the sensitivity due to the noise of nonspecific binding. Alternating current (AC) electrokinetics and its effect on biosensing is an increasing field of research dedicated to addres...

Microfluidic dielectrophoretic (DEP) devices enable the label-free separation and isolation of cells based on differences in their electrophysiological properties. The technique can serve as a tool in clinical diagnostics and medical research as it facilitates the analysis of patient-specific blood composition and the detection and isolation of pat...

In einem übertrieben kompetitiven System der Forschungsförderung bleibt angesichts der Bürokratie immer weniger Zeit für die Forschung. In an excessively competitive system of research funding, the bureaucracy leaves less and less time for research.

As an alternative to standard silicon biofunctionalization protocol based on alkoxysilanes that bind to SiO2 on oxidized silicon substrates, several protocols to form bifunctional interlayers that directly bind to the silicon surface via a strong Si-C bond have been developed during the last decades. These interlayers are more stable, and the lack...

In this paper the importance of correct impedance matching is discussed in dielectrophoresis (DEP) experiments with commercial signal generators. An uncompensated and a 50 Ω terminated setup are compared to an approach utilizing an active in-line buffer with low output impedance. The losses in effective signal amplitude are simulated for different...

Finite Element Method is used to model the voltage drop inside dielectrophoresis actuators. Frequency dependence is investigated for varying electrochemical conditions and actuator geometries. A hands-on equation to calculate the operation cut off frequency with respect to the electrode geometry is derived. Lumped element modeling is validated by v...

Microalgae are investigated due to their high production rates of useful biochemical compounds like polyunsaturated fatty acids (PUFA). The present work demonstrates separations of cells from PUFA-producing microalgae species Crypthecodinium cohnii which is developed in comparison to well defined polystyrene-carboxylate microbeads of different size...

The combination of extreme miniaturization with a high sensitivity and the potential to be integrated in an array form on a chip has made silicon-based photonic microring resonators a very attractive research topic. As biosensors are approaching the nanoscale, analyte mass transfer and bonding kinetics have been ascribed as crucial factors that lim...

Microalgae biotechnology has a high potential for sustainable bioproduction of diverse high-value biomolecules. Some of the main bottlenecks in cell-based bioproduction, and more specifically in microalgae-based bioproduction, are due to insufficient methods for rapid and efficient cell characterization, which contributes to having only a few indus...

Inertial microfluidic systems have been arousing interest in medical applications due to their simple and cost-efficient use. However, comparably small sample volumes in the microliter and milliliter ranges have so far prevented efficient applications in continuous bioprocesses. Nevertheless, recent studies suggest that these systems are well suite...

Mikroalgen können als biologische Mikrosysteme von meist sphärischer Gestalt mit Durchmessern von wenigen bis zu einigen 100 μm aufgefasst werden. Abb. 1 zeigt ein Ensemble von Aurantiochytrium sp. Zellen mit Durchmessern ab 15 bis 40 μm. Als Produzenten von hochwertigen, mehrfach ungesättigten Fettsäuren sind sie als vielversprechender Rohstoff fü...

Dielectrophoresis (DEP) is a promising technology for cell separation and sorting of microalgae. In this work, DEP is used in the cell separation of Chlamydomonas reinhardtii (a microalga that is useful in the production of biofuel) based on their lipid content inside a microfluidic setup. COMSOL Multiphysics is used to determine the correct proces...

Microalgae biomass is considered as a source of lipids in the production of pharmaceuticals, nutrients, and renewable biofuels. Dielectrophoresis (DEP) has evolved as an interesting technology allowing the vital, impeccable, and label-free cell sorting of microalgae in microfluidic systems. In this work, COMSOL Multiphysics 5.4 is used to find the...

Mikroalgae as alternative producers for biofuels, nutrients and pharmaceuticals came in the focus of biotechnology. Cells with different lipid content may be separated by dielectrophoresis (DEP) in microfluidic channels without subjecting them to staining for fluorescence detection. The poster reports of simulations with finite-element methodes (FE...

A microelectronic biosensor was subjected to in vivo exposure by implanting it in the vicinity of m. trapezii (Trapezius muscle) from cattle. The implant is intended for the continuous monitoring of glucose levels, and the study aimed at evaluating the biostability of exposed semiconductor surfaces. The sensor chip was a microelectromechanical syst...

An affinity-viscometry-based micro-sensor probe for continuous glucose monitoring was investigated with respect to its suitability for bioprocesses. The sensor operates with glucose and dextran competing as binding partner for concanavalin A, while the viscosity of the assay scales with glucose concentration. Changes in viscosity are determined wit...

The era of Quality by Design (QbD) in industrial process monitoring requires new approaches for data analysis, i.e. on‐line data collection and analysis. Raman spectroscopy has a great potential for on‐line bioprocess monitoring that has not yet been realized due to limitations including (i) high threshold value for most analytes due to the high fl...

The integration of two 32 GHz permittivity sensing chips, fabricated in a 0.13 µm SiGe BiCMOS technology, into microwell plates on a printed circuit board (PCB) is presented. The microchip displayed in Fig. 1 has a total size of 2.1mm², consumes 127mW of power and features on-chip DC readout. The sensing circuit is a resonator based oscillator, whi...

Biotechnology and biopharmaceutical production have an increasing demand of monitoring in the era of quality by design approaches in industrial scale, requiring manufacturing capabilities of a previously unknown sophistication. This sophistication comes at a great cost – and new approaches are required to gain data rapidly and of sufficient quality...

With the growing demand of miniaturization of cell cultivation a new approach towards measuring and sensing bio-analytes needs to be made due to the problem of small volumes (less than 150μl) containing small amounts of analytes. Most of the available glucose sensors monitor the glucose concentration with the help of enzymes, which become very inac...

An integration concept for an implantable biosensor for the continuous monitoring of blood sugar levels is presented. The system architecture is based on technical modules used in cardiovascular implants in order to minimize legal certification efforts for its perspective usage in medical applications. The sensor chip operates via the principle of...

The capabilities of modern semiconductor manufacturing offer remarkable possibilities to be applied in life science research as well as for its commercialization. In this review, the technology modules available in micro‐ and nano‐electronics are exemplarily presented for the case of 250 and 130 nm technology nodes. Preparation procedures and the d...

Modern technological devices to a large extent rely on polycrystalline thin films. This holds for instance for integrated circuits from the semiconductor industry, sensoric and optical layers to mention only a few examples. Often, polycrystalline films exhibit pronounced gradients, i.e. depth-dependent evolutions of fiber texture and residual stres...

Die Forschung und Entwicklung hat zwischen 2007 und 2012 die Anzahl an Tierversuchen um 15,3% reduzieren können. Über einen Zeitraum von 29 Jahren sank die Anzahl sogar um 69,5%. Im Mittelpunkt stand nicht nur die Verkleinerung der Tierversuchsgruppen sondern auch die Entwicklung von Alternativen zu Tierversuchen. Potentielle alternative Methoden s...

An intelligent sensor implant for continuous glucose monitoring is presented as intended for use in the human interstitial. The sensor operates by the principle of affinity viscosimetry, by which glucose concentrations are determined with a microelectromechanical system (MEMS) measuring the glucose-dependent viscosity of a concanavalinA-dextran ass...

A path loss estimation for 403 MHz MICS band antennas based on measurements in body phantom liquid is presented. Suitable antennas were identified that can be used in medical implants. A reproducible measurement setup has been tested that allows for a quantitative comparison of different implant antennas.

A path loss determination for 403 MHz MICS band antennas based on measurements in body phantom liquid is presented. Suitable antennas were identified that can be used in medical implants. A reproducible measurement setup has been tested that allows for a quantitative comparison of different implant antennas.

A major challenge in biomaterials research is the regulation of protein adsorption which is a key factor for controlling the subsequent cell adhesion at implant surfaces. The aim of the present study was to control the adsorption of fibronectin (FN) and the attachment of MG-63 osteoblasts with an electronic nanostructure. Shallow doping line lattic...

Surface materials of an implantable microelectronic chip intended for medical applications were evaluated with respect to their long-term stability in bio-environments. The sensor chip shall apply in a glucose monitor by operating as a microviscosimeter according to the principle of affinity viscosimetry. A monolithic integration of a microelectrom...

The theoretical evaluation of an implantable system measuring glucose for diabetes diagnostics and therapy has recently been presented. This work reports on the realisation of the proposed system on a printed circuit board and measurements of its energy budget. It is shown that the system can be run with small 3.2 V batteries for more than six mont...

A fabrication process of ultrathin TiN micro-electromechanical systems (MEMS) actuators intended for applications in electrostatic actuator schemes is presented. It includes the preparation of the TiN layer from the back end of line (BEOL) module of a 0.25 μm bipolar complementary metal oxide semiconductor (BiCMOS) technology. Furthermore, the proc...

Ein minimal-invasiver Glucose-Affinitätssensor für den transdermalen Einsatz wird beschrieben. Die Signalbildung beruht auf der von der Glucosekonzentration abhängigen Viskosität einer sensitiven Flüssigkeit, in der Dextranmoleküle durch das tetravalente Lektin Concanavalin A reversibel vernetzt sind. Die Viskositätsmessung erfolgt in einer mit der...

Latest developments in micro-electro-mechanical systems (MEMS) have paved the way to follow the more than Moore approach. Several key components, such as silicon pressure sensors have been developed using MEMS processing techniques. Recently, MEMS technologies have been combined with standard CMOS processes and MEMS devices such as microviscosimete...

A standard complementary metal-oxide-semiconductor (CMOS) process is successfully modified to encompass the preparation of suspended TiN membranes of only 50 nm thickness from one of the metal layer stacks of the back-end flow. The layers’ elastomechanical constants are determined with high precision by laser Doppler vibrometry. Residual stress gra...

This paper presents a backside-to-frontside alignment technique for the backside processing of Si wafers. Integrated MEMS components like BiCMOS-embedded RF-MEMS switches require accurate (1-2 mu m) alignment. We demonstrate an alignment technique providing overlay values of less than 500 nm by using a backside alignment layer. The approach is enab...

Silicon films were grown on (100) n-Si with an electron-cyclotron resonance chemical vapor deposition (ECRCVD) system by decomposition of SiH at 325 C. Structure and composition of thin films were investigated by SEM, Raman spectroscopy, elastic recoil detection analysis (ERDA) and TEM. Excellent epitaxial growth was achieved for some hundred nm th...

Intelligente Implantate gewinnen zunehmend an Bedeutung. Sie zeichnen sich durch eine möglichst weitgehende Miniaturisierung und einen geringen Energiebedarf aus. Die Kleinheit des Systems ist wichtig für seine Akzeptanz beim Patienten und eine medizinisch wenig aufwändige Implantationstechnik. Der geringe Energiebedarf ist wichtig für die Lebensda...

The use of the dominant CMOS (complementary metal–oxide–semiconductor) process technology in perspective bioelectronic applications imposes severe restrictions on the materials used with respect to their stability in aqueous solutions with high concentrations of electrolytes. We report the results of a comparative study of Al:Cu, CoSi2 and TiN meta...

A microchip separation process operating by pulsed-wave IR laser irradiation was applied to microviscosimeters that are intended to operate as glucose sensors for continuous monitoring of blood sugar levels in diabetics. After its technological preparation the sensor should no more dry up, since the retreating water would stick a movable cantilever...

A novel approach for the investigation of proteins or macromolecules is outlined in this conceptual study. The preparation of grapho-epitaxial layers on nanotemplated substrates is proposed as an alternative to the preparation of single crystals by vapour diffusion techniques. Crystal structure investigations of such layers may then be performed vi...

Different MEMS process techniques have been integrated to 0.25 μm BiCMOS process. First developed technique is Back-End-Off-Line (BEOL) integration. This technique was developed using standard metallization layers of BiCMOS process with an additional MEMS process steps. An RFMEMS capacitive switch was realized using BEOL embedded MEMS module. Back-...

We demonstrate for the first time the embedded integration of a Radio Frequency Microelectromechanical Systems (RF-MEMS) capacitive switch for mm-wave integrated circuits in a BiCMOS Back-end-of-line (BEOL). The switch shows state-of-the-art performance parameters. The ¿off¿ to ¿on¿ capacitance ratio is 1:10 providing excellent isolation in the mm-...

Die fortgeschrittene Miniaturisierung mikroelektronischer und mikrosystemtechnischer Bauteile ermöglicht bereits heute die Entwicklung neuartiger medizin- und biotechnologischer Systeme, die durch hohen Tragekomfort für den Patienten und verminderte Analysekosten gekennzeichnet sind. Insbesondere auf dem Gebiet der point-of-care Diagnostik, die die...

Die Mikroelektronik ist zu einem unverzichtbaren technischen Bestandteil moderner menschlicher Gesellschaften geworden. Seit Einführung der ersten integrierten Schaltungen in den 60er Jahren hat sie einen atemberaubenden Wettlauf zu immer kleineren Strukturen vollzogen, die mit ihr herzustellen sind – und das nicht nur an wenigen Exemplaren, sonder...

Preferred crystallographic orientation or texture is a typically observed phenomenon in polycrystalline thin films. In addition, texture was revealed in numerous x-ray diffraction studies to increase with layer thickness. The phenomenon is rather significant for the optimized preparation of thin films, but was difficult to measure so far. A method...

The geometry of crystalline bonding in pyrite-structure disulfides MS2 is investigated for the M = Mn, Fe, Co, Ni, Cu series. The decomposition of interatomic distances by the ionic radii approach is first shown to yield metal ion values rM inconsistent with state-of-the-art data. The bonding geometry is subsequently analyzed by assuming sulfur ion...

Anomalous X-ray diffraction is applied to the quantitative determination of fiber texture gradients. Use is made of a theoretical model, in which crystallographic texture is described by an order parameter n and the depth dependent n(z) is assumed to follow a linear behavior (M. Birkholz, 2007, J. Appl. Cryst., 40, 735). The presented method is bas...

The nanopatterning of semiconductor surfaces and the subsequent preparation of bio-semiconductor hybrid devices on such surfaces will enable the application of new principles of biomolecular sensing. Nanopatterning may be achieved due to decreasing minimum feature dimensions by various techniques well established in CMOS processing. Here, the prepa...

Crystallographic textures in thin polycrystalline films typically exhibit a rotational symmetry, i.e. they occur as a fibre texture with the texture pole being orientated in direction of the substrate normal. As a further characteristic of thin film textures it was often observed that the degree of preferred orientation increases with increasing th...

Line and cross lattices of 260 and 360 nm pitch were prepared by covering p-doped Si(100) substrates with photoresist, structuring and implanting with 3 × 1015 cm–2, 45 keV As+ ions. These doping lattices with n+–p periodicity were investigated by X-ray diffraction (XRD) and reflectivity (XRR). While XRD did not show any signal of the periodic stru...

The organic–inorganic interface and its proper structural adjustment are of central importance for the fabrication of hybrid material systems from biomolecules and semiconductors. Such material hybrids are currently under development for several advanced applications, in particu-lar for biomolecular sensing. An investigation of biomolecular immobil...

Defined placement of biomolecules at Si surfaces is a precondition for a successful combination of Si electronics with biological applications. We aim to realize this by Coulomb interaction of biomolecules with dislocations in Si. The dislocations form charged lines and they will be surrounded with a space charge region being connected with an elec...