Researchers have conquered the monumental task of manufacturing scalable nanoprobe arrays small enough to record the inner workings of human cardiac cells and primary neurons.
The ability to read electrical activities from cells is the foundation of many biomedical procedures, such as brain activity mapping and neural prosthetics.
Developing new tools for intracellular electrophysiology (the electric current running within cells) that push the limits of what is physically possible (spatiotemporal resolution) while reducing invasiveness could provide a deeper understanding of electrogenic cells and their networks in tissues, as well as new directions for human-machine interfaces.
In a paper published by Nature Nanotechnology, scientists from Surrey’s Advanced Technology Institute (ATI) and Harvard University detail how they produced an array of the ultra-small U-shaped nanowire field-effect transistor probes for intracellular recording.
This incredibly small structure was used to record, with great clarity, the inner activity of primary neurons and other electrogenic cells, and the device has the capacity for multi-channel recordings.
Dr Yunlong Zhao from the ATI at the University of Surrey said:
“If our medical professionals are to continue to understand our physical condition better and help us live longer, it is important that we continue to push the boundaries of modern science in order to give them the best possible tools to do their jobs.
For this to be possible, an intersection between humans and machines is inevitable.
“Our ultra-small, flexible, nanowire probes could be a very powerful tool as they can measure intracellular signals with amplitudes comparable with those measured with patch clamp techniques; with the advantage of the device being scalable, it causes less discomfort and no fatal damage to the cell (cytosol dilation).
Through this work, we found clear evidence for how both size and curvature affect device internalisation and intracellular recording signal.”
Professor Charles Lieber from the Department of Chemistry and Chemical Biology at Harvard University said:
“This work represents a major step towards tackling the general problem of integrating ‘synthesised’ nanoscale building blocks into chip and wafer scale arrays, and thereby allowing us to address the long-standing challenge of scalable intracellular recording.
“The beauty of science to many, ourselves included, is having such challenges to drive hypotheses and future work.
In the longer term, we see these probe developments adding to our capabilities that ultimately drive advanced high-resolution brain-machine interfaces and perhaps eventually bringing cyborgs to reality.”
Professor Ravi Silva, Director of the ATI at the University of Surrey, said:
“This incredibly exciting and ambitious piece of work illustrates the value of academic collaboration.
Along with the possibility of upgrading the tools we use to monitor cells, this work has laid the foundations for machine and human interfaces that could improve lives across the world.”
Dr Yunlong Zhao and his team are currently working on novel energy storage devices, electrochemical probing, bioelectronic devices, sensors and 3D soft electronic systems. Undergraduate, graduate and postdoc students with backgrounds in energy storage, electrochemistry, nanofabrication, bioelectronics, tissue engineering are very welcome to contact Dr Zhao to explore the opportunities further.
To continue the remarkable success of semiconductor technology and possibly produce new paradigms for logic, memory and sensor devices, many researchers have been investigating devices based on synthesized nanostructures(2,5,7–12) in which geometries, organizations and physical properties can be designed and controlled at the nanometer scale.
A wide spectrum of nanostructured materials have been designed and synthesized over the past several decades, including colloidal nanoparticles(13,14), semiconductor nanowires (NW)(3,4,15,16), and graphene(10,17–20), where properties distinct from their bulk counterparts have been discovered and exploited.
For any class of nanostructured materials to become a platform for discovery and development, it is critical that new structures and assemblies with tunable composition, morphology, and properties at different length scales be obtainable(3,10,18).
In this regard, semiconductor nanowires have been recognized as one of the most successful platforms available today in nanoscience.
First, it is now possible to design nanowire structures de novoand synthetically realize these structures with complex, yet controlled, modulations in composition(8,16,21–26), doping(16,23), defect(27–29) and even topography(30–32).
Third, it is now possible to assemble hybrid or multicomponent functional materials in novel layout and configuration using these diverse nanowire building blocks(31,33–45), allowing for rational exploration of the possible applications of multi-component materials.
With these characteristics and capabilities, nanowires are ideal building blocks for exploring what is possible in nanoscience and also creating new technologies.
In particular, the exploration and application of semiconductor nanowire materials and devices in cellular systems could produce unprecedented interactions down to the molecular level.
Such interactions have been utilized to gain insights especially those relevant to human health by stimulating, recording from and delivering objects to single cells and tissues in controlled ways to induce desired physiological responses, while minimizing undesirable effects(52,53).
There are two types of nanowire-based platforms in biomedical sciences: basic platforms that can be readily adapted to address biomedical questions; and advanced platforms that are specifically designed to push the frontiers of what is possible by, for example, enabling a new measurement tool.
The basic platforms use conventional nanowire material and device systems with well-exploited physical or chemical properties, and they also have wide-ranging applications in many other fields, such as energy scavenging systems(54–61) or components for integrated circuit(34,35).
These basic platforms, such as planar nanowire field effect transistors(34,35,37,40,43) or vertical nanowire arrays(55–58,60,61), have been used in biomolecular sensing(52,53), extracellular recording(52,53), drug delivery(62–64) and localized cellular imaging(65). On the other side, the advanced platforms have been designed to address some intrinsic complexity in biology and medical sciences in way simply not possible previously.
This review discusses the basic concepts of nanoscale field effect transistors (nanoFETs) and their applications in cellular electrophysiology.
The first section highlights the motivation behind nanoFET probes to study cellular systems versus existing recording technologies, followed by the introduction of chemical synthesis to realize nanoFETs de novo.
The second section gives an overview of the current progress in multiplexed extracellular sensing using planar nanoFET arrays.
Electrical recordings at single cell, tissue and organ levels will be discussed, and their limits and promises will be delineated.
The third section will detail the main designs and implementations of nanoFETs in intracellular electrical recording from single cells, the first paradigm change in intracellular electrophysiology since the 1950s.
NanoFET based techniques will be compared with conventional micropipette and microelectrode probes, and the limits and future opportunities of these new probes will be discussed.
The fourth section will introduce very recent progress in merging electronic and biological systems at the 3D tissue level by introducing the new concept of macroporous nanoelectronic scaffolds.
The first-ever nanoelectronics ‘innervated’ synthetic tissues will be reviewed and their applications will be discussed.
The final section will present our perspectives on future development in this research area, the unique challenges and opportunities, and the tremendous impact these nanoFET based technologies might have in advancing biology and medical sciences.Go to:
FUNDAMENTALS OF NANOFET
Why and how are nanoFETs applied in biology and medicine?
The ability to make electrical measurements inside single cells or throughout the entire 3D space of the tissue can have many important impacts in electrophysiology and biomedical sciences.
The patch clamp technique, in which a pulled glass micropipette filled with electrolyte is inserted into a cell, offers intracellular electrical measurements with high signal-to-noise ratio (S/N) and single ion channel recording capability(70).
Ideally, the micropipette should be as small as possible to increase the spatial resolution and reduce the invasiveness of the measurement, and ideally, allow for recording from subcellular structures.
However, the overall performance of the technique also depends on the impedance of the interface between the micropipette and the cell interior (i.e., the smaller the probe tip size, the larger the junction impedance), which sets limits on the temporal resolution and S/N of the micropipette-based electrical probes(31,41).
Advanced techniques that involve inserting metal or carbon microelectrodes or nanoelectrodes into cells or tissues could be subject to similar dilemma, because all these tools are single terminal devices and electrochemical thermodynamics and kinetics must be considered for device operation(71–78). We will discuss them in details in the subsequent sections.
Although the charge carriers are ions in biological systems, there are many biophysical links that connect ions to electrons and holes in a FET.
For example, the dynamic flow of ions in biological system can generate spatially defined field potential(80).
The Poisson equation(81) links such potentials directly to the ionic current sources and sinks that produce them.
The Goldman-Hodgkin-Katz voltage equation(81) has also been used in cell membrane physiology to determine the equilibrium potential across a cell’s membrane, where it takes into account all of the ions that permeate through that membrane.
The potentials, generated by ion flows and gradients, can function as the gate signals to modulate the electrical output in FET devices (Figure 1b and 1c).
The sensitivity of a FET or how well the transistor can receive and amplify the gate signal is usually defined as transconductance (Gm)(6,52,53,79), which is inversely proportional to the dimension (L) of the active device(6).
This fact implies that the use of nanoelectronics would have improved sensitivity compared to its bulk and planar counterparts.
As shown in the following sections, nanoFETs have shown to be able to record electric potentials inside cells(31,67–69) and from the internal regions of synthetic tissues(66), and because their performance does not depend on impedance, they can be made much smaller than micropipettes and microelectrodes.
Chemical synthesis of nanoFETs
Three distinct classes of de novo design and synthesis have been used to yield nanoFETs building blocks , covering structural motifs in one-dimension (1D), 2D and 3D (Figure 2).
The basic semiconductor nanowire structure (Figure 2a, I) consists of a uniform composition, 1D structure with a diameter typically in the range of 3–500 nm.
In the growth process, which builds upon earlier work showing vapor-liquid-solid (VLS) growth of micrometer to millimeter diameter wires(82,83), the nanocluster catalyst (typically gold nanoparticles) forms a liquid solution with nanowire reactant component(s), and when supersaturated, acts as the nucleation site for crystallization and preferential 1D growth(84,85).
Other growth mechanisms, such as vapor-solid-solid (VSS) and vapor-solid (VS)(15), can also be explored to yield high quality semiconductor nanowires.
Within this framework, it is straightforward to synthesize nanowires with different compositions, such as groups III-V, IV and II-VI semiconductors(8,15,86,87), using the appropriate nanocluster catalysts and growth temperatures/pressures.
Additionally, nanowire structures in which the composition, dopant and even growth mechanisms (e.g., VLS, VSS) are modulated along axial(21,22,88–90) (Figure 2b) or radial directions(25,29,91)have also been widely exploited.
These axial and radial nanowire heterostructures provide a number of advantages compared to homogeneous semiconductor nanowires, and they have proven exceptionally powerful for a broad range of electronic, photonic and optoelectronic device applications(16).
For example, germanium/silicon core/shell nanowires have been chemically synthesized for high mobility nanowire FETs due to quantum confinement of carriers within the germanium core by the larger band-gap silicon shell(5,92–95).
In this area, we demonstrated that iterative control over nucleation and growth leads to kinked nanowires, in which the straight sections are separated by triangular joints and where doping can be varied at these topologically defined points (Figure 2c).
Moreover, new work has shown that it is possible to control the stereochemistry of adjacent kinks in a manner that allows the synthesis of increasingly complex two- and three-dimensional structures akin to organic chemistry, thus opening up a great opportunity for the future in terms of designed synthesis(31).
To this end, we reported a rational, multistep approach toward the general synthesis of 3D branched nanowire heterostructures(24).
Single-crystalline semiconductor, including groups IV, III–V, and II–VI, and metal branches have been selectively grown on core or core/shell nanowire backbones, with the composition, morphology, and doping of core (core/shell) nanowires and branch nanowireswell controlled during synthesis.
Although the first structural motif has been used most extensively as building blocks of basic platforms, the second and third motifs have much higher level of structural and functional complexity, and show great potential of bottom-up synthesis to yield increasingly powerful functional building blocks for advanced platforms.
- Yunlong Zhao, Siheng Sean You, Anqi Zhang, Jae-Hyun Lee, Jinlin Huang, Charles M. Lieber. Scalable ultrasmall three-dimensional nanowire transistor probes for intracellular recording. Nature Nanotechnology, 2019; DOI: 10.1038/s41565-019-0478-y