Scalable hybrid microelectronic-microfluidic integration of highly sensitive biosensors
Authors: Reinecke Patrick , Putze Marie-Theres , Georgi Leopold , Kahle Ruben , Kaiser David , Hüger Daniel , Livshits Pavel , Weidenmüller Jens , Weimann Thomas , Turchanin Andrey , Braun Tanja , Becker Karl-Friedrich , Schneider-Ramelow Martin , Lang Klaus-Dieter 
Published: December 2018

Abstract
Point of Care devices for medical applications are becoming more and more widespread. The advantage of having test results after a very short period and without any laboratory creates is beneficial for doctors in developing countries far away from laboratory infrastructure to clinical devices disburdening in-house laboratories for example in case of an outbreak of an epidemic. Especially infectious diseases are one of the world's leading cause of morbidity and death [1]. Viral respiratory infections are a major cause of burden of disease in children. Annual human respiratory syncytial virus (RSV) related death are around 253.000, mainly in developing countries. It accounts for up to 6.7 % of mortality of children younger than 1 year. Therefore, RSV is the second most important global cause of death during infancy. Furthermore, RSV infection has been linked to an increased risk in the development of childhood wheezing and asthma in later life [2, 3]. Fast and cheap diagnostic, independent from laboratory infrastructure, will have a high impact on the healthcare system. Highly sensitive microelectronic biosensors have a superior sensitivity and accuracy compared to paper stripes. The higher miniaturization potential and production stability accompanied by a better readout simplicity makes them a cheaper alternative to optical systems.
In this paper a hybrid microelectronic-microfluidic packaging strategy for a disposable for two different microelectronic biosensor platforms will be presented, targeting the diagnostic of RSV. The multiplexed detection of both, host and pathogen biomarkers in the same sample will lead to a rapid, cheap and accurate diagnosis and prognosis, providing almost real-time results.
Platform 1, the BioGrFET sensor uses a graphene field effect transistor (GrFET). The liquid sample containing the biomarkers flows over the sensor's surface with probe molecules, where the target molecules (specific biomarkers) of the fluid can be immobilized. The charge of the biomarker on the surface changes the charge carrier density inside the graphene which can be detected by measuring the graphene field effect transport characteristic.
Platform 2, the BioMEMS sensor is a micro electro mechanical system (MEMS) having a very thin membrane carrying the active sensor structure, offering additional challenges to device packaging. The liquid sample, containing the biomarkers, flows over the membrane's surface with detection molecules, where the specific biomarkers of the fluid can be immobilized. With the specific biomarkers on the membrane's surface changes the mass and therefore the resonance frequency of the membrane which can be read out.
Specific packaging challenge for both sensors is to develop packaging technology flows that allow to add the sensor functionalization during packaging and leaves this functionalization intact until the packaging processes are finalized, which implies a process selection with reduced thermal and mechanical load on the delicate functionalized sensors. This challenge has been mastered for both sensors – yielding two dedicated packaging process flows that were used to manufacture functional sensor packages.