Printable Molecule-Selective Nanoparticles Enable Mass Production of Wearable Biosensors

The future of medicine may very well lie in the personalization of health care—knowing exactly what an individual needs and then delivering just the right mix of nutrients, metabolites, and medications, if necessary, to stabilize and improve their condition. To make this possible, physicians first need a way to continuously measure and monitor certain biomarkers of health.

To that end, a team of Caltech engineers has developed a technique for inkjet printing arrays of special nanoparticles that enables the mass production of long-lasting wearable sweat sensors. These sensors could be used to monitor a variety of biomarkers, such as vitamins, hormones, metabolites, and medications, in real time, providing patients and their physicians with the ability to continually follow changes in the levels of those molecules.

Wearable biosensors that incorporate the new nanoparticles have been successfully used to monitor metabolites in patients suffering from long COVID and the levels of chemotherapy drugs in cancer patients at City of Hope in Duarte, California.

"These are just two examples of what is possible," says Wei Gao, a professor of medical engineering in the Andrew and Peggy Cherng Department of Medical Engineering at Caltech. "There are many chronic conditions and their biomarkers that these sensors now give us the possibility to monitor continuously and noninvasively," says Gao, who is the corresponding author on a paper in the journal Nature Materials describing the new technique.

Gao and his team describe the nanoparticles as core–shell cubic nanoparticles. The cubes are formed in a solution that includes the molecule that the researchers want to track—for example, vitamin C. As the monomers spontaneously assemble to form a polymer, the target molecule—vitamin C—is trapped inside the cubic nanoparticles. Next, a solvent is used to specifically remove the vitamin C molecules, leaving behind a molecularly imprinted polymer shell dotted with holes that have shapes exactly matching that of the vitamin C molecules—akin to artificial antibodies that selectively recognize the shapes of only particular molecules.

Importantly, in the new study, the researchers combine those specially formed polymers with a nanoparticle core made of nickel hexacyanoferrate (NiHCF). This material can be oxidized or reduced under an applied electrical voltage when in contact with human sweat or other bodily fluids. Returning to the vitamin C example, fluid will come into contact with the NiHCF core as long as the vitamin C–shaped holes are unoccupied, and this will generate an electrical signal.

When vitamin C molecules come into contact with the polymer, however, they slip into those holes, thus preventing sweat or other bodily fluids from making contact with the core. This weakens the electrical signal. The strength of the electrical signal, then, reveals just how much vitamin C is present.

"This core is critical. The nickel hexacyanoferrate core is highly stable, even in biological fluids, making these sensors ideal for long-term measurement," says Gao, who is also a Heritage Medical Research Institute Investigator and a Ronald and JoAnne Willens Scholar.

The new core-shell nanoparticles are highly versatile and are used in printing sensor arrays that measure levels of multiple amino acids, metabolites, hormones, or drugs in sweat or bodily fluids simply by using multiple nanoparticle "inks" in a single array. For example, in the work described in the paper, the researchers printed out nanoparticles that bind to vitamin C along with other nanoparticles that bind to the amino acid tryptophan and creatinine, a biomarker commonly measured to see how well the kidneys are working. All of the nanoparticles were combined into one sensor that was then mass produced. These three molecules are of interest in studies of patients with long COVID.

Similarly, the researchers printed out nanoparticles-based wearable sensors that were specific to three different antitumor drugs on individual sensors that were then tested on cancer patients at City of Hope.

"Demonstrating the potential of this technology, we were able to remotely monitor the amount of cancer drugs in the body at any given time," Gao says. "This is pointing the way to the goal of dose personalization not only for cancer but for many other conditions as well."

In the paper, the team also showed that the nanoparticles can be used to print sensors that can be implanted just below the skin to precisely monitor drug levels in the body.

The lead authors of the paper, "Printable molecule-selective core–shell nanoparticles for wearable and implantable sensing" are Minqiang Wang and Cui Ye of Caltech. Additional authors are Yiran Yang (PhD '23), Daniel Mukasa (MS '21), Canran Wang (MS '23), Changhao Xu (PhD '24), Jihong Min (PhD '24), Samuel A. Solomon (MS '23), Jiaobing Tu (PhD '24), and Songsong Tang of Caltech; Guofang Shen and Jeannine S. McCune of the Beckman Research Institute at City of Hope; and Tzung K. Hsiai and Zhaoping Li of the David Geffen School of Medicine at UCLA. The work was supported by funding from the National Science Foundation, the National Institutes of Health, the American Cancer Society, the Office of Naval Research, the Army Research Office, a NASA Cooperative Agreement, the Heritage Medical Research Institute, and the Caltech-City of Hope Biomedical Initiative. The Kavli Nanoscience Institute at Caltech provided critical support and infrastructure for this project.