
Nanomaterials are widely used in medicine. They make up the biocompatible scaffolds in artificial wound grafts, the regenerative coatings in dental implants and many bioelectronic interfaces in other medical devices. Yet in recent years, another use for nanomaterials has come into focus: researchers are developing nanomaterial-based biosensors for applications ranging from diagnosing infectious agents to discovering biomarkers and tracking health metrics like glucose levels.
Traditional biosensors usually suffer from low sensitivity and limited dynamic range. In other words, they perform poorly when the molecule to be detected is present at low concentrations or in too wide a range of concentrations. Applying nanomaterial-based biosensing alleviates these limitations.
For one, the surface area-to-volume ratio shoots up astronomically at the nanoscale. This means there’s much more room where the analytes – the substance or chemical compound being measured – can bind. When the sensing relies on a chemical reaction, the large surface area translates to high reactivity and, consequently, faster reaction times. This allows for quick detection of analytes like ions, lipids and proteins, among others. Additionally, nanomaterials exhibit unique mechanical and optical properties.
“The effect of the nanoscale introduces a whole new set of properties,” says Tony Cass, professor of chemical biology at Imperial College London. “Which can either improve the sensitivity of existing materials or open up completely new ways of making measurements.”
The gold standard
Rapid testing kits are the most commonly available sensors that use nanomaterials for biosensing. These kits use lateral flow assays to detect pregnancies, Covid-19 or allergen sensitivity, among others. They use nanoparticles – typically, gold nanoparticles (GNPs) – to achieve high sensitivity and specificity in analyte detection. In clinical settings, similar GNPbased biosensors are used to identify biomarkers for different diseases like cancers and cardiovascular diseases. “We use gold nanoparticles to either increase the surface area [for signal detection] or to enhance the signal,” says Pedro Estrela, director of the Centre for Bioengineering and Biomedical Technologies at the University of Bath. In the latter case, the gold nanoparticles tug at the target molecules to make them more detectable.
Gold nanoparticles are the gold standard for medical biosensors for good reason: they have unique optical and electrochemical properties that make them suitable for rapid visual biosensing. When electrons hit gold nanoparticles, they emit scattered light at particular wavelengths – a phenomenon known as surface plasmon resonance. Modifying the shape and size of gold nanoparticles changes the emitted spectra, allowing design of biosensors that detect specific molecules and can change in colour in response. Plus, the high conductivity of gold and the nanoparticle structure facilitate ultrafast electron transport between different electrodes and materials. GNP-based biosensors typically leverage one or both of these properties to detect analytes.
Researchers are also developing biosensors that tap into other interesting properties of GNPs. For example, piezoelectric biosensors convert stress or strain into electric currents and can detect even the slightest changes in mass during biomolecular interactions. Another approach under investigation is hybridising gold nanoparticles with other materials or nanomaterials to boost the chemical stability or versatility of GNP biosensors.
In addition to using GNPs for detecting different analytes, researchers are looking for ways to optimise and automate their synthesis. A key aim here is to lower the cost of nanoparticle synthesis, which is often the limiting step in the fabrication of GNP biosensors.
Carbon-based biosensing
In recent years, graphene has received a lot of attention in the field of nanomaterial-based biosensing. “Whether it’s for sensing infectious disease agents or monitoring biomarkers associated with diabetes, cardiovascular disease, or cancer, it is one of the first go-to materials in many different biosensors,” says Cass. Graphene is an allotrope of carbon that exists as a sheet of a single layer of carbon atoms arranged in a honeycomb lattice.
The distinct composition of graphene gives it interesting properties. Mechanically, it is incredibly strong, despite being an atom thick, yet flexible. That means that you can add sensors to its surface without hurting its structural integrity. Optically, it exhibits plasmon surface resonance and is sensitive enough to detect single cells. The 2D material combines extremely high conductivity and low charge carrier resistance (meaning electrical current passes through easily) which enables ultrasensitive detection of biological signals. Estrela also sees great potential in using arrays of graphene-based sensors, most notably in field effect transistors (FET). These are semiconductor biosensors that do not need fluorescent probes or expensive optical instruments. This convenience, together with the ease of integration with other technologies and the flexibility of graphene, makes them suitable for use in wearables. Because of the thinness and high chemical stability of graphene, graphene FET biosensors have superior electrical performance compared to other FET biosensors.
However, despite the hype around it, graphene has its limitations. For instance, the process of synthesising graphene is complicated, while the surface chemistry between graphene and different probes is not as well understood as that for nanoparticles and, as a result, graphene biosensing is not as robust and reproducible. Though graphene is highly sensitive to environmental fluctuations and, consequently, can pick up extremely weak signals amidst biological noise.
Another approach to carbon-based nanomaterials is to roll carbon, typically graphene sheets, into nanotubes. While the electrical and optical properties of carbon nanotubes are comparable to graphene’s, the former’s geometry permits greater electron transfer and signal transduction. Beyond carbon, scientists are exploring nanotubes made from silicon, nitrides, and peptides – each offering different opportunities for what they could detect.
Other advances
Although metal nanoparticles, graphene and nanotubes remain the most studied nanomaterials for biosensing, scientists are testing a range of new options, too. Some of these include metal oxide nanoparticles, nanowires and DNA or RNA-based biosensors. Advancements in nanomaterials promise improvements in biosensors’ catalytic efficiency (how well they speed up a chemical reaction), specificity and biocompatibility.
Take nanozymes, for instance. These are nanomaterials that mimic the presence of enzymes. Whereas enzymes need to be stored under the right conditions and degrade over time, neither of those constraints apply to nanozymes. Additionally, Estrela says, “Using nanostructures or nanoparticles to catalyse specific analytes is promising because we don’t need to fabricate the electrodes or add any biology to it.” However, there is a need for precise control over the conditions under which the measurement is performed.
One active area of research is enhancing the sensitivity of nanomaterial-based biosensors to be able to detect single molecules. This will enable the detection of trace elements and reveal structural interactions of biomolecules. Multiplexed biosensing, or being able to simultaneously detect different analytes, is another frontier that could revolutionise precision medicine. Designing biosensors that eliminate molecular noise and cross-interference from different analytes will help realise these possibilities.
“One of the main advances in recent times has been creating nanostructured electrodes that have a very high density of probes,” says Estrela. These involve using nanomaterials to add or carve out nanoscale structures on electrode surfaces. Compared to conventional electrodes, nanostructured electrodes achieve lower limits of detection and wider dynamic ranges.
But new nanomaterials may improve biosensors in ways beyond detecting, amplifying, or transducing signals. For example, they could also help reduce power consumption, which is key in developing wearable or implantable biosensors. “This relies on advances in electronics, which in turn take advantage of nanoscale phenomena,” says Cass.
Scaling nanomaterial biosensors
As is often the case, technology adoption is influenced by factors beyond the technology itself. For instance, the Covid-19 pandemic strengthened the case for wider clinical use of commercially available biosensors. “I think the push toward telemedicine and [users’] acceptance of testing themselves is going to change the number of biosensor tests that are going to be out there,” says Estrela. Nanomaterial-based biosensing could usher in the development of diagnostic kits for a range of different medical use cases but, Estrela adds, they need to be easy to use and affordable.
This underlies the need for slashing the cost of producing nanomaterials. While researchers are fashioning a host of new nanomaterials and applying them to ever-new use cases, most are hard to produce at scale. Researchers are investigating ways to bring down the costs of generating nanomaterials, including producing them in microbes or using microfluidics to make synthesis more efficient and reproducible.
However, these approaches are still in their infancy, and production costs need to drop significantly for these technologies to be adopted at scale. Equally, for new nanomaterial-based biosensing technologies to successfully translate to commercially available sensors, they will need to replicate performance metrics achieved in the lab when they’re produced at scale.
Here, scaling the synthesis of nanomaterials alone isn’t enough, as nanomaterials are only part of what makes a biosensing system. “For each component of the system, you try and pick properties that match the clinical diagnostic need, and the components have to be manufacturable and come in at the right price point and pass all the regulatory barriers,” says Cass.
Nanomaterials are poised to have a huge impact on how biosensors are designed and what they are used for. But, stresses Cass, “it’s the whole systems approach that’s really important.”