Anqi Zhang

Specific detection of biomolecules in physiological solutions using graphene transistor biosensors

Significance Nanoelectronic transistor sensors based on synthesized one- and two-dimensional nanomaterials have achieved real-time label-free detection of a wide range of biological species with high sensitivity, although direct analysis of biological samples has been limited due to Debye charge screening in physiological solutions. This paper describes a general strategy overcoming this challenge involving comodification of the transistor sensor surface with a polymer and receptor, where the polymer forms a permeable layer that increases the effective screening length and receptor enables selective detection of analytes. The capability of this strategy was demonstrated with selective detection of cancer markers in physiological solution, thus opening substantial opportunities for real-time sensing applications in biology and medicine. Nanomaterial-based field-effect transistor (FET) sensors are capable of label-free real-time chemical and biological detection with high sensitivity and spatial resolution, although direct measurements in high–ionic-strength physiological solutions remain challenging due to the Debye screening effect. Recently, we demonstrated a general strategy to overcome this challenge by incorporating a biomolecule-permeable polymer layer on the surface of silicon nanowire FET sensors. The permeable polymer layer can increase the effective screening length immediately adjacent to the device surface and thereby enable real-time detection of biomolecules in high–ionic-strength solutions. Here, we describe studies demonstrating both the generality of this concept and application to specific protein detection using graphene FET sensors. Concentration-dependent measurements made with polyethylene glycol (PEG)-modified graphene devices exhibited real-time reversible detection of prostate specific antigen (PSA) from 1 to 1,000 nM in 100 mM phosphate buffer. In addition, comodification of graphene devices with PEG and DNA aptamers yielded specific irreversible binding and detection of PSA in pH 7.4 1x PBS solutions, whereas control experiments with proteins that do not bind to the aptamer showed smaller reversible signals. In addition, the active aptamer receptor of the modified graphene devices could be regenerated to yield multiuse selective PSA sensing under physiological conditions. The current work presents an important concept toward the application of nanomaterial-based FET sensors for biochemical sensing in physiological environments and thus could lead to powerful tools for basic research and healthcare.

Spontaneous Internalization of Cell Penetrating Peptide-Modified Nanowires into Primary Neurons

Semiconductor nanowire (NW) devices that can address intracellular electrophysiological events with high sensitivity and spatial resolution are emerging as key tools in nanobioelectronics. Intracellular delivery of NWs without compromising cellular integrity and metabolic activity has, however, proven difficult without external mechanical forces or electrical pulses. Here, we introduce a biomimetic approach in which a cell penetrating peptide, the trans-activating transcriptional activator (TAT) from human immunodeficiency virus 1, is linked to the surface of Si NWs to facilitate spontaneous internalization of NWs into primary neuronal cells. Confocal microscopy imaging studies at fixed time points demonstrate that TAT-conjugated NWs (TAT-NWs) are fully internalized into mouse hippocampal neurons, and quantitative image analyses reveal an ca. 15% internalization efficiency. In addition, live cell dynamic imaging of NW internalization shows that NW penetration begins within 10-20 min after binding to the membrane and that NWs become fully internalized within 30-40 min. The generality of cell penetrating peptide modification method is further demonstrated by internalization of TAT-NWs into primary dorsal root ganglion (DRG) neurons.

Nanowire Field-Effect Transistor Sensors

Sensitive and quantitative analysis of proteins and other biochemical species are central to disease diagnosis, drug screening and proteomic studies. Research advances exploiting SiNWs configured as FETs for biomolecule analysis have emerged as one of the most promising and powerful platforms for label-free, real-time, and sensitive electrical detection of proteins as well as many other biological species. In this chapter, we first briefly introduce the fundamental principle for semiconductor NW-FET sensors. Representative examples of semiconductor NW sensors are then summarized for sensitive chemical and biomolecule detection, including proteins, nucleic acids, viruses and small molecules. In addition, this chapter discusses several electrical and surface functionalization methods for enhancing the sensitivity of semiconductor NW sensors.

Nanoelectronics, Circuits and Nanoprocessors

As electronic device features have been pushed into the deep sub-100-nm regime, conventional scaling strategies in the semiconductor industry have faced technological and economic challenges. Electronics obtained through the bottom-up approach of molecular-level control of material composition and structure may lead to devices and fabrication strategies as well as new architectures not readily accessible or even possible within the context of the top-down driven industry and manufacturing infrastructure. This chapter presents a summary of recent advances in basic nanoelectronics devices, simple circuits and nanoprocessors assembled by semiconductor NWs.

Hierarchical Organization in Two and Three Dimensions

The rationally designed and synthesized semiconductor NWs offer as a platform material with the potential to realize unprecedented structural and functional complexity as building blocks. To utilize these building blocks for nanoscale devices through integrated systems, for example in electronics and photonics, requires controlled and scalable assembly of NWs on either rigid or flexible substrates. In this chapter, we will summarize recent advances in large-scale NW assembly and hierarchical organization with two general approaches. First, organization of pre-grown NWs onto target substrates in one or more independent steps, where distinct NW building blocks can be used in each assembly step, and second, the direct growth of aligned NWs on substrates will be discussed.

Nanowire Interfaces to Cells and Tissue

The interface between nanosystems and biosystems is emerging as one of the broadest and most dynamic areas of science and technology, bringing together biology, chemistry, physics and many areas of engineering, biotechnology and medicine. The combination of these diverse areas of research promises to yield revolutionary advances in healthcare, medicine and the life science through, for example, the creation of new and powerful tools that enable direct, sensitive and rapid analysis of biological species and cellular activities. Research at the interface between nanomaterials and biology could yield breakthroughs in fundamental science and lead to revolutionary technologies. In this chapter, we will introduce studies focused on building the interface of NWs to cells and tissues, including extracellular and intracellular signal recording, synthetic cyborg tissues and in vivo recording.

Emergence of Nanowires

The design, development and understanding of synthetic materials, with at least one dimension below 100 nm, have been driving a broad range of research in the scientific community for a number of years given the potential of such materials to substantially impact many areas of science and technology. In particular, one-dimensional nanowires, with diameters reaching to the molecular or quantum regime, have been a focus of research over the past two decades. The underlying principles for synthesis of one-dimensional materials have been investigated in different contexts for almost half a century ago, although significant challenges existed in developing the critical understanding to control (i) diameters to the deep nanoscale dimensions as well as (ii) structure and composition in the axial and radial coordinates as necessary for the synthesis of materials with designed and tunable functionality. In this chapter, the emergence of the nanowire research platform is introduced, including the concept and importance, synthetic challenges and initial design, and the development of vapor-liquid-solid crystal growth mechanism. In addition, other nanofabrication based approaches explored in the early years of this field will be briefly introduced.

Nanowire-Enabled Energy Conversion

Substantial recent scientific effort has been focused on the development of renewable energy sources, such as solar energy, in order to lower the carbon footprint for energy usage. Semiconductor NWs are attractive candidates for energy conversion materials since their composition, size and other factors that determine basic electronic and optical properties can be synthetically manipulated in complex ways. In this chapter, we discuss representative NW-based structures and devices for energy conversion, particularly focusing on photovoltaic, thermoelectric, and piezoelectric systems that have been used produce energy by converting light, heat, and mechanical sources.

General Synthetic Methods

Over the past two decades, remarkable progress has been made in research focused on the synthesis of 1D NWs leading to the rational design and synthetic control of key properties, where the capability of design and control of NWs has opened up the potential for revolutionary advances in diverse areas ranging from electronics and photonics to energy and healthcare. Scaling NW diameters to the deep nanometer and even molecular regime, as well as controlling their morphology, composition and structure represents fundamental challenges critical to exploiting NWs for applications in science and technology. In this chapter, we overview major bottom-up strategies for the synthesis of NWs, including vapor phase, templated, and solution-based methods. The advantages and challenges of different methods will be discussed, with representative examples illustrated.

Structure-Controlled Synthesis

Advances in nanoscience and nanotechnology critically depend on the development of nanostructures whose properties are controlled during synthesis. The ability to control and modulate the composition, doping, crystal structure and morphology of semiconductor NWs allows researchers to explore applications of NWs for investigating fundamental scientific questions through developing new technologies. The chapter expands significantly upon the basic methods introduced in the previous chapter for NW synthesis by focusing on controlled growth of a host of NWs with modulated morphologies and structures, including axial and radial heterostructures, kinked, branched, and/or modulated doped structures, where the increased complexity in the NWs can enable unique functional properties.