2025 Symposium on
VLSI Technology and Circuits

Workshop 6

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Recent Advances in CMOS Cellular and Molecular Biosensors

Organizer : Hua Wang (ETH Zurich)
Organizer : Drew Hall (UC San Diego)

Over the past two decades, we have seen remarkable advancements in the use of CMOS integrated circuits (ICs) to develop integrated biosensors and bioelectronics. Modern CMOS IC technologies provide unmatched device performance, high integration density, and advanced computational capabilities, driving continuous innovation in integrated bioelectronics at the circuit level. Simultaneously, increasing investments in CMOS-compatible post-processing technologies have significantly broadened the functionalities of CMOS bioelectronics. As a result, CMOS biosensors are experiencing rapid growth and finding applications in diverse areas, including neural interfaces, gas sensors, and intelligent sensor arrays that directly interact with cells and molecules. This workshop aims to showcase recent advancements in CMOS-based cellular and molecular sensors and foster discussions on the future technology directions of this dynamic field.


About Organizers

Organizer:Hua Wang is a Full Professor and the Chair of Electronics at D-ITET of ETH Z?rich. He is also the Institute Deputy Head of the Integrated Systems Laboratory (IIS). Prior to that, he was a Tenured Associate Professor at the School of ECE at Georgia Institute of Technology, USA. He worked at Intel Corporation and Skyworks Solutions from 2010 to 2011. He received his M.S. and Ph.D. degrees in electrical engineering from the California Institute of Technology, Pasadena, in 2007 and 2009, respectively.
Dr. Wang is interested in analog, mixed-signal, RF, and mm-Wave integrated circuits and hybrid systems for communication, sensing, and bioelectronics. He is an IEEE Fellow. He has authored or co-authored over 250 peer-reviewed journal and conference papers.

Co-Organizer: Drew A. Hall is a Full Professor at the Department of Electrical and Computer Engineering at the University of California at San Diego (UCSD). Prior to joining UCSD, he was a Research Scientist in the Integrated Biosensors Laboratory at Intel Corporation. He received the B.S. degree in computer engineering with honors from the University of Nevada, Las Vegas in 2005, and the M.S. and Ph.D. degrees in electrical engineering from Stanford University in 2008 and 2012, respectively.
His research interests include bioelectronics, biosensors, analog circuit design, medical electronics, and sensor interfaces. Dr. Hall is a Tau Beta Pi Fellow. He has served as an Associate Editor of the IEEE TRANSACTIONS ON BIOMEDICAL INTEGRATED CIRCUITS since 2015, a member of the CICC Technical Program Committee from 2017-2024, a member of the ISSCC Technical Program Committee since 2020, and an Associate Editor of the IEEE Solid-State Circuits Letters from 2021 to 2024.

1. Multi-Modal CMOS Biosensing and Actuation: Advancing Cellular and Molecular Diagnostics, Hua Wang, ETH Zurich

Abstract:
This workshop presentation introduces the state-of-the-art multi-modal CMOS biosensing and actuating platforms for multi-parametric cellular and molecular analysis. Featuring arrays with up to 21,952 multimodal pixels at single-cell and subcellular resolution, these systems integrate multiple sensing modalities—impedance tomography, pH sensing, electrochemical detection, and ion-selective imaging—and actuation functions such as dielectrophoresis and current stimulation. Validated with human and mouse progenitor cells, as well as SARS-CoV-2 RNA, these CMOS multi-modal bio-sensing/actuation platforms enable high-throughput characterization of cellular behavior, drug responses, and ion channel activity. Innovations like in-pixel biosensing/actuation circuits, antifouling surfaces, and robust current-to-digital conversion ensure biocompatibility, scalability, and environmental noise resistance. We will explore applications in organ-on-chip systems, personalized diagnostics, and molecular disease modeling, gaining insights into how these technologies will potentially advance biophysical and biochemical analyses at unparalleled resolution and throughput.

2. Continuous Monitoring of Small Molecules Using Electrochemical Aptamer-Based Biosensors with CMOS Electronic, Jun-Chau Chien, University of California

Abstract:
The ability to continuously monitor specific molecules over extended periods can provide fundamentally new insights into disease dynamics and the transition from a healthy to a diseased state. This capability can also drive the development of next-generation screening and detection tools. However, only a few biomolecules—such as glucose, oxygen, and dopamine—can currently be monitored in real time due to multiple limitations in existing biosensor technologies. In this presentation, we introduce a class of biosensors known as aptamers. Aptamers are synthetic antibodies composed of nucleic acids (e.g., DNA or RNA) that can specifically bind to target analytes in complex samples, including whole blood. Importantly, they can be engineered into aptamer switches, which undergo reversible structural changes upon target binding. By conjugating electroactive reporters to these aptamers, structural changes—correlated to analyte concentration—can be detected electrochemically. Because aptamer switches do not require sample preparation, they are well-suited for continuous in vivo monitoring of biomolecules. However, integrating these structure-switching aptamers with readout electronics presents unique challenges. We will first outline the biosensor requirements and present our circuit innovations to meet them. This will be followed by discussion on system-level integration with wireless capabilities tailored for wearable and implantable applications. We will also address challenges such as signal drift and biofouling. Finally, we will demonstrate successful continuous monitoring of small-molecule drugs, such as antibiotics and chemotherapeutics, in freely moving rodents.

3. Neuronal synaptic connectivity mapping by CMOS microchip, Donhee Ham, Harvard University

Abstract:
Intracellular recording of a neuron is sensitive and can measure small synaptic signals. Massive parallelization of neuronal intracellular recording is an important pursuit in neuroscience––because it can allow for the measurement of synaptic signals in quantity across a neural network and thus can help search and characterize synaptic connections in the network–– but was previously difficult. We have been developing CMOS electrode arrays that can massively parallelize intracellular recording. This has culminated in our recent 4,096 microhole electrode array operated by an underlying CMOS integrated circuit, which achieves a 90% average intracellular coupling rate with mammalian neurons (Nature Biomed. Eng., 2025). From the resulting network-wide intracellular recording data that teem with synaptic signals, not only have we found 70,000+ plausible synaptic connections amongst 2,000+ neurons, but we have also been able to characterize and catalogue them. This scale of physical synaptic connectivity mapping is an advance relevant to the functional––as opposed anatomical––connectivity mapping of the brain. I will present this advance with the historical background and how it can be useful not only in neuroscience but also for neuromorphic engineering and brain-machine interface.

4. A Scalable CMOS Molecular Electronics Chip for Single-Molecule Biosensing, Drew Hall, University of California, San Diego

Abstract:
This work reports the first CMOS molecular electronics chip, where the primary sensing element is a single molecule “molecular wire” consisting of a ∼100 GΩ, 25 nm long alpha-helical peptide integrated into a current monitoring circuit. The engineered peptide contains a central conjugation site for attachment of various probe molecules, such as DNA, proteins, enzymes, or antibodies, which program the biosensor to detect interactions with a specific target molecule. The current through the molecular wire under a dc applied voltage is monitored with millisecond temporal resolution. The detected signals are millisecond-scale, picoampere current pulses generated by each transient probe-target molecular interaction. Implemented in a 0.18 µm CMOS technology, 16k sensors are arrayed with a 20 µm pitch and read out at a 1 kHz frame rate. The resulting biosensor chip provides direct, real-time observation of the single-molecule interaction kinetics, unlike classical biosensors that measure ensemble averages of such events. This molecular electronics chip provides a platform for putting molecular biosensing “on-chip” to bring the power of semiconductor chips to diverse applications in biological research, diagnostics, sequencing, proteomics, drug discovery, and environmental monitoring.

5. Cyber-Secure Biological Systems, Rabia Tugce Yazicigil, Boston University

Abstract:
This talk will introduce Cyber-Secure Biological Systems, leveraging living sensors constructed from engineered biological entities seamlessly integrated with solid-state circuits. This unique synergy harnesses the advantages of biology while incorporating the reliability and communication infrastructure of electronics, offering a unique solution to societal challenges in healthcare and environmental monitoring. In this talk, examples of Cyber-Secure Biological Systems, such as miniaturized ingestible bioelectronic capsules for gastrointestinal tract monitoring and hybrid microfluidic-bioelectronic systems for environmental monitoring, will be presented. These collaborative research projects involve MIT BE/MechE and BU ECE/BME.

6. Panel Discussion