application in diagnostics and imaging nanowire biosensors

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They are used mainly for the electrical detection of single viruses and biomolecules (Patolsky et al., 2004). Nanowire biosensor is a Field Effect Transistor (FET) in which the metal gate oxide is replaced by molecular receptors that are capable of binding to specific charged species resulting in channel conductance. They are linear wires with 20-100nm in size and exhibit super conductivity and high sensitivity to electric fields. When charged molecules in the sample (e.g., Virus) bind to the nanowire receptors, the conductance is changed from baseline value and is retained when the virus unbinds from the receptor (figure 1). The sample is delivered in the microfluidic channel confined to the central region coupled with nanowires, where the sample flows at a constant rate and the conductance is recorded. Multiple viruses can be detected simultaneously at a single particle level by modifying the receptor specific nanowires within an array. Silicon Nanowires (SiNW) proved to be efficient in creating real time extremely sensitive sensors for the quantitative detection of biological species (Cui et al., 2001). Detection of small molecule protein kinases that are responsible for chronic myelogenous leukemia (Wang et al., 2005) and real time label free detection of DNA and DNA mismatches is also feasible with SiNW FET devices (Hahm and Lieber, 2004).

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Figure: Nanowire based sensors operating within a microfluidic system. Different colours represent different viruses/molecules affinity-bind or adsorb to their respective nanowire sensors. The conductance caused due to the binding is recorded electronically. It works on the principle of a (biologically) gated transistor. High signal to noise ratios are attained by the nanosize of the wire. (Source: Nature review Cancer, Ferrari 2005)

Cantilevers:

Cantilever arrays are engineered to aid in disease diagnosis. They convert physical or biological processes into recordable electrical signal in nanoelectromechanical systems (NEMS) or microelectromechanical systems (MEMS) (Hansen et al., 2005). Disease associated molecules such as proteins, DNA sequences and single-nucleotide polymorphisms are bound to these arrays. When these molecules are adsorbed on the surface of cantilever, the changes in surface tension causes the cantilever beam to bend demonstrating the presence of the disease associated molecules. Cantilevers also serve as a good diagnosing tool for high throughput genomic analysis and proteomics for detecting early molecular events in disease development. Recently the microcantilever based multiplex DNA assays to detect mutations have been introduced (Chen et al., 2004). Even though the use of nanoparticle probes result in individual single-pair mismatch discrimination, the cantilever arrays yet do not offer significant advantages over conventional ones. Multiplexing modality, the ability to detect different proteins at the same time is the breakthrough potential in cantilever technology. Hence, it is realistic to envision the simultaneous reading of the proteomic profiles or the entire proteome by a single centimetre sized chip which is constructed of thousands of cantilever arrays. Currently, Protiveris Inc., based in USA is developing microfluidic optical reader (VeriScanTM 3000) that uses microcantilever arrays to measure distinct biomolecular interactions between proteins, antibodies, antigens or DNA.

Figure: Cantilever Array Senor. The binding of the biomarkers to the cantilevers cause them to bend. Lasers are used to directly observe the deflections of the cantilever beams. Alternatively, the shift in resonance frequencies caused by binding can be electronically detected. (Source: Nature Cancer Review, Ferrari 2005)

Nanoparticle based Biosensor:

The early screening and diagnosis of the disease in the patients require ultra-sensitive detection tests. Conventional protein or antigen detection methods (eg., ELISA, blotting assays) are relatively insensitive to the target and hence are not effective in detecting the diseases at early stages. Recently, an ultra-sensitive, multiplex and low volume biomarker analysis called bio barcode assay has been developed for antigen/protein detection (Nam et al., 2003). The assay uses two types of probes: magnetic nanoparticle probes functionalised with monoclonal antibody and gold nanoparticle probes functionalised with polyclonal antibodies and hundreds of hybridised oligonucleotides (Barcode DNA). These monoclonal and polyclonal antibodies identify and bind to the target protein, sandwiching it between micro- and nano particles (Figure). A magnetic field is applied to remove the sandwich from solution and barcode DNA probes are released into the solution which are then analysed using standard DNA detection methods. This technology has been successfully applied as a breast cancer screening target for detecting PSA (Prostate Specific Antigen) at low concentrations (Black et al., 2000) and also for the detection of amyloid-β-derived diffusible ligands in cerebrospinal fluid of Alzheimer's patients (Georganopoulou et al., 2003).

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Figure: Bio Barcode assay. a) Probe Design and Preparation b) a magnetic probe captures a target using either monoclonal antibody or complementary oligonucleotide. Target-specific gold nanoparticles sandwich the target and account for target identification and amplification. The barcode oligonucleotides are released and detected using the scanometric method. (Source: Nam, Science 2003)

In vivo Imaging:

Magnetic Resonance Imaging (MRI): MRI has evolved as an important in vivo diagnostic tool in clinical radiology. To image the molecular constituents of the pathological processes directly by MRI, sensitive and site-targeted contrast agents are required. To date, Nanoparticles are the most successful MRI contrast agents available to image the small molecular constituents. Nanoparticles like Paramagnetic metals, Superparamagnetic substances, Fullerenes and Dendrimers are used as contrast agents in MRI (Lanza at al., 2004). Now-a-days the iron oxide nanoparticles are commercially available in the market. For example, Advanced Magnetics, Inc. is manufacturing Lumirem® (loops of bowels) and Endorem™ (Liver lesions). Supravist™ (Scheiring AG) and Sinerem® (Roissy, France) are two ultra small superparamagnetic iron oxide (USIPO) particles that are under development. Luna Innovations Inc. (USA) is developing fullerene based nanoparticles (Trimetaspheres™) which are expected to provide enhanced images 25 times better than the commercially available ones.

Nuclear Imaging: In nuclear imaging, the patient's body is administered with a radionuclide agent whose uptake by organs depends upon their metabolism. These agents allow the imaging of the physiological processes. In nanotechnology-based nuclear imaging, Nanoparticles are attached to the radionuclides to provide contrast that allows SPECT imaging. For example, Kereos, USA is developing tumour specific contrast agent Technetium-99 which consists of perflurocarbon nanoparticles (Rollo, 2003). Other companies such as DOW chemical and Philips medical are also developing nanoparticle-based contrast agents that will provide quantitative measurements of the disease processes.

Ultrasound Imaging: It is used for delivering the morphological information about organs and tissues. Currently available ultrasound imaging agents consist of gas filled microbubbles (1-2µm) which are considered on the upper boundary of nanodimensions (Unger et al., 2004). For example, Definity® (ImaRex Therapeutics Inc., USA), Optison™ (Amersham Biosciences, UK) and SonoVue® (Astra Tech AB, Sweden) are commercially available gas filled microbubbles for diagnostic imaging. At present only limited research work on nanosized ultrasound contrast agents is taking place and none of them have reached clinical trials yet.

Optical Imaging: Quantum Dots (QDs) are the most prolific nanotech-based optical contrast agents. QDs are first used for in vivo studies in 2002 to trace the cell lineages in frog embryos (Dubertret et al., 2002). Ever since they are being used to image cancer markers (Wu, 2003), Tumours in living animals (Gao, 2004) and in Cell Signal Transductions (Lidke, 2004). These experiments allowed researchers to believe that there is a realistic chance for QD technology in medical in vivo imaging. However, the high toxicity of the semiconductor materials used in QD manufacturing is the main roadblock for reaching the goals.