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Nanoscale biosensor lets scientists monitor molecules in real time

Wouldn't it be amazing if we could continuously monitor the molecular state of our body? Consider the solutions that could enable, from optimized drug delivery to early detection of deadly diseases like cancer.

For the last two decades, research has aimed to make this a reality by developing devices that measure a chemical or biological reaction in our bodies and send their measurements as a signal readable from outside the body. These devices, called biosensors, can now spot tiny molecules like drugs in real time, but they work only briefly. There is still no single reliable biosensor that can monitor many different substances in our bodies over long stretches.

To address this limitation, researchers at Stanford have now engineered a modular biosensor called the Stable Electrochemical Nanostructured Sensor for Blood In situ Tracking (SENSBIT) system, which has remained fully functional for up to a week when implanted directly into the blood vessels of live rats.

In a paper in Nature Biomedical Engineering, the Stanford research team showed that SENSBIT could continuously track drug concentration profiles. The team obtained maximum signal efficacy in both live rat models and human serum.

Gut check

Over the span of a decade, researchers in Soh's lab designed a molecular switch that could bind to small molecules of interest in the body to give a readable signal output to continuously measure the molecules' concentrations. These switches by themselves are prone to degradation due to the body's natural immune responses.

To help prevent this issue, in their previous work, the team "hid" the switches in nanoporous electrodes. Signals from these electrodes could then measure the drug levels inside the tumor of a live rat for the first time. Despite the effort, this technology still could not last long enough inside an organism due to immune system attacks.

"We needed a material system that could sense the target while protecting the molecular switches, and that's when I thought, wait, how does biology solve this problem?" said Yihang Chen, the first author of the paper, who conducted this work while earning his Ph.D. in materials science and engineering under Soh.

Chen and his team took inspiration from the human gut, designing the SENSBIT system to mimic the gut's natural defenses. Like microvilli lining the intestinal wall, the sensor's 3D nanoporous gold surface shields its sensitive elements from interference while a protective coating modeled after gut mucosa helps prevent degradation. This bioinspired design allows SENSBIT to remain stable and sensitive even after many days of continuous exposure to flowing blood inside living animals.

Upon testing SENSBIT, the Chen team found it retained over 70% of its signal after one month in undiluted human serum (the part of the blood that remains after cells and clotting factors are removed) and over 60% after spending a week implanted in the blood vessels of live rats. As far as the researchers know, the previous limit for intravenous exposure for this type of device was 11 hours, whereas SENSBIT lasted 7 days. SENSBIT could thus deliver reliable, real-time molecular monitoring in complex biological fluids.

A new approach to reading our biology

Our bodies have a very coordinated playbook of what to do when a virus, bacteria, or any other invader tries to disrupt our natural system. If we could understand how the body is coordinating using these molecules, we could potentially pick up infections before any symptoms arise.

Using the SENSBIT system is not the only strategy for continuous molecular monitoring; still, it does seem to be significantly better than any similar devices that have been tested in blood.

Continuous molecular monitoring could open the door to a new medical paradigm—one where we can not only detect disease earlier but also potentially tailor treatments in real time.

"I believe our work contributes to laying the foundation for this future," Chen said, "and I'm motivated by the opportunity to help push those boundaries forward."

Soh is the W. M. Keck Foundation Professor in Electrical Engineering. He is also a member of Stanford Bio-X, the Wu Tsai Human Performance Alliance, the Maternal & Child Health Research Institute, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute, and a faculty fellow of Sarafan ChEM-H.

Additional Stanford co-authors include former postdoctoral fellow Kaiyu Fu, former veterinary resident Renee Cotton, former postdoctoral scholar Zihao Ou, postdoctoral scholar Jean Won Kwak, former research engineer Jun-Chau Chien, former postdoctoral scholar Vladimir Kesler, former postdoctoral scholar Hnin Yin Yin Nyein, and Michael Eisenstein, an affiliate of the Department of Electrical Engineering.