Nanoelectromechanical Systems Improved Medical Diagnostics For Personalised Medicine Biology Essay

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When we twang a guitar string it vibrates and as it does so it forces the air around it into the motion, giving rise to sound we hear. The string finally stops moving because as it sets the air in motion about it, it loses energy and so slows down. This project is about the behavior of tiny strings, called nanomechnical resonator, which are about a million times smaller than a guitar string. The frequency or pitch that comes from string depends on how long the string is. in guitar the frequency is just right for humans hear it, but for the nanomechnical resonators the frequency is much higher same as radio waves, so well as our beyond our hearing.nanomechnical resonator can be used as extremely sensitive set of weighing scales, because nanomechnical resonator itself very small weigh like a beliological virus.

The term Nanoelectromechanical systems or NEMS is used to describe devices integrating electrical and mechanical functionality on the nanoscale. NEMS form the logical next miniaturization step from so-called microelectromechanical systems, or MEMS devices. NEMS normally integrate transistor-like nanoelectronics with mechanical actuators, pumps, or motors, and may so form physical, biological, and chemical sensors. The name derives from typical device dimensions in the nanometer range, leading to low mass, high mechanical resonance frequencies, potentially large quantum mechanical effects such as zero point motion, and a high surface to volume ratio useful for surface-based sensing mechanisms.[1]

Uses include accelerometers, or detectors of chemical substances in the air.

there are a lot of potential applications of machines at smaller and smaller sizes; by building and controlling devices at smaller scales, all technology benefits. Among the expected benefits include greater efficiencies and reduced size, decreased power consumption and lower costs of production in electromechanical systems.

Introduction.

There is increasing interest in improved medical diagnostics for personalised medicine and the early detection of disease. Ideally, these devices would feature high sensitivity, few false positive or negative readings, and the capability for large scale multiplexing.

By monitoring a core set of biomarkers, the onset of common diseases or those to which the patient is genetically susceptible can be monitored, moving towards the ultimate of early detection. Such devices could supplant current tests and provide a better platform for individualised medicine. Micro- and nanoelectromechanical systems (MEMS and

NEMS) are one such technology that has the potential to achieve these goals, and many devices are currently being applied as biosensors for detection of infectious agents and disease biomarkers.[2] The small size and high sensitivity of MEMS and NEMS suggests that they are good candidates for miniaturized sensor systems and amenable to multiplexed detection through the use of arrays of devices that could be uniquely functionalized and feature on-chip redundancy for detection of each analyte.

When used in sensing applications, the added analyte material can induce a surface stress, causing tip deflection in the case of static mode sensors, or change the mechanical properties or the mass of the devices, resulting in a resonant frequency shift for

Dynamic mode sensors.

Brief Description.

In general, micro- and nanomechanical resonators can be modeled like harmonic oscillators with a resonant frequency, f, given by f f (D 1/m)/0.5, where D is the flexural rigidity and m is the resonator mass.[3] Changes in flexural rigidity, given by the product of material stiffness and the second moment of the crosssectional area, have been observed for deposition of relatively stiff films on cantilevers.[4] However for the detection of soft biomolecules, flexural rigidity changes will likely be negligible. In this regime, only changes in mass will dictate resonant

frequency shifts. For small changes in mass, relative frequency shifts can be approximated as

where Dm/m is the ratio of added mass, Dm, to the initial resonator mass, m, n is 1 or 2 based on whether mass is added to one or both sides of the resonator, s is the mass per unit area of the added material, and r and t are the density and thickness of the resonator, respectively. The frequency response, given by the quantity Df/f, is used here rather than absolute frequency shift because it is unaffected by variations in the initial frequency, f,

from device to device due to slight differences in the fabricated structures. From Eqn (1), it is evident that thinner and less dense resonators make the best mass sensors. Resonators used in this work are trampoline shaped, unlike the traditional cantilever geometry found ubiquitously in the literature; an SEM micrograph of the arrayed devices is shown in

Fig. 1(a). Recent work has demonstrated that cantilevers are not always the most sensitive geometry and that trampoline-like resonators have a relatively uniform frequency response for the mass of bound material located anywhere across its central

paddle because of its unique resonant mode shape.[5] Such a uniform response across much of the sensing area would be desirable for the detection of dilutely added materials, as it would reduce variations from device to device caused by randomly distributed binding events. This effect motivated the use of paddlever resonators in recent work for the detection of prion proteins,and trampolines represent the next logical step in

improving the uniformity of the positional mass sensitivity. The trampoline centre has a diameter of 6 mm, and the support arms are 1 mm wide. These flexible supports allow the centre to move in and out of plane with fairly constant amplitude and help to concentrate the majority of the device sensing area in the region most sensitive to mass loading, the central paddle.6 This motion is depicted in Fig. 1(b), showing the extent of trampoline

displacement for the fundamental resonant mode, which is used in this work. In addition, the large surface area of these devices, ~54 mm2, is significantly greater than that of the previously used 4 mm long paddlevers, ~30 mm2,or cantilevers of the same

length,~ 8 mm2, increasing the probability of capturing analytes at extremely low concentrations, which may improve sensitivity. As a model biomarker for our resonant sensors, we use prostate specific antigen (PSA), a clinically monitored protein used in

Fig. 1 (a) SEM micrograph of 3 3 arrays of trampoline resonators with 50 mm between adjacent devices. The centre area of each device measures 6 mm in diameter, with a 1 mm dia. hole at the centre for etching purposes. (b) Image obtained using finite element analysis depicting the displacement of the device in the fundamental resonant mode.

screening tests for prostate cancer.8 PSA is a normally produced protein found at a high concentration in seminal fluid. Elevated concentrations of PSA in the blood are associated with a higher risk for prostate cancer and may indicate damage of the prostate

tissue, allowing PSA to escape into circulation.9 While PSA can be found in its free form, it is more common for it to be complexed with enzymes or other molecules, such as a1-chymotrypsin, a1-protease inhibitor, or a2-macroglobulin. At this time, sensitivity to total PSA (free and complexed) concentrations in the range of 2 to 10 ng m/L are required, as there is elevated risk for prostate cancer at these concentrations, while for free PSA the clinically relevant concentrations range from 0.5 to 1.2 ng m/L (15-36 pM).[6] When PSA is found at or above these concentrations, a biopsy is often required as the next step to assess whether the increased concentration is associated with prostate cancer or another condition such as benign prostate hyperplasia. However, many

such biopsies are negative for cancer; it has been suggested that monitoring the percentage of free to complexed PSA may be more sensitive and also avoid unnecessary biopsies by helping to discern between benign and malignant conditions.[7] With

improved sensitivity to PSA levels in serum, its concentration could be tracked over a long period of time at lower concentrations, and increased risk could be gauged from case to case by personal baselines and trends rather than approximate, agebased

cut-off guidelines. Several groups have used MEMS or NEMS sensors in order to detect PSA, such as blood serum, urine, or saliva, as sensors applied in the medical field would face these solutions every day. One recent study using micromechanical resonators to detect PSA has tried to combat this with using prolonged washing after serum has been introduced to the devices, which appeared to remove a large part of the non-specifically bound material.[8] In serum, they observed signal reduction and a detection limit of 100 pg m/L, however, no explicit data from control measurements was shown, which is required to determine the effect of the background media on the sensors and the detection limit. In this work we use a sandwich assay-based, secondary mass labelling technique in order to detect PSA. Arrays of trampoline resonators were functionalised with capture antibodies specific to PSA, and a second antibody was used to specifically tether nanoparticle mass labels to PSA molecules attached to the devices. These devices demonstrated PSA detection from undiluted serum at concentrations ranging from 50 ng m/L down to 50 fg m/L, or 1.5 fM.

Device Fabrication.

Devices were fabricated using standard lithographic techniques for surface

micromachining. Clean silicon wafers were thermally oxidised to form a 1.8 mm thick sacrificial layer of silicon dioxide. Following oxidation, a 90 nm thick layer of low stress silicon nitride was grown on the wafer. Resonator designs were then patterned using photolithography and an anisotropic, CF4-based reactive ion etch chemistry. Next, chips containing thousands of arrayed resonators each were diced from the wafer. Device chips

were then etched with hydrofluoric acid in order to remove the sacrificial oxide layer so that the resonators would be free to move. The hole in the device centre was required to etch the silicon dioxide beneath the trampoline and fully release the devices. Critical point drying was not required at any point in the device fabrication or surface modification because the sacrificial oxide layer was sufficiently thick as to avoid stiction phenomena. Device chips were loaded into a small vacuum chamber mounted to a motorised stage, and the resonant frequencies were measured in vacuum at pressures <10/3 Torr. The resonators were mechanically excited into resonance by mounting them on an external piezoelectric element driven at the resonant frequencies of devices. Clean, freshly released devices had resonant frequencies of roughly 2.2 MHz and quality factors of ~6000. A HeNe laser (632.8 nm) was focused at the centre of the trampolines and used to interferometrically detect device resonance. Laser power delivered to each device was kept at a minimum (typically on the order of 50 mW) in order to minimise

heating effects. The reflected signal was collected using a fast photodetector and read out using a spectrum analyser. A custom-built graphic user interface program has been developed to control the stage and the spectrum analyser, allowing automated

readout of an array of devices in minutes. In this work, frequency shifts were measured using many devices from different arrays on each chip, and the average frequency

responses were considered, while error bars are determined by the standard deviations.

Surface chemistry

In order to specifically capture PSA on resonators and detect their presence, a sandwich immunoassay was performed on device surfaces. After HF release, chips were cleaned for 30 minutes in a 2:1 piranha solution (concentrated sulfuric acid to 30% hydrogen peroxide) and then for 30 minutes in an oxygen plasma. Devices were functionalised with 3-aminopropyltriethoxysilane (APTES, Sigma, 99%) overnight (~16 hours) using a 10% solution in dry toluene (Sigma, 99.8%) in a moisture-free environment. Following silanisation, the device chips were washed in a series of acetone, isopropanol, and water,

and then soaked in DI water for 15 minutes on an orbital shaker in order to remove excess APTES. Surface modification continued by soaking chips in a 5% solution of gluteraldehyde (Sigma, 50%) in borate buffer for 2 hours, serving as a covalent

cross-linker molecule between the amine groups on the silanised surface and antibodies. Following this and all subsequent steps, device chips were washed twice in purified DI water on an orbital shaker operating at 95 RPM. Each washing step was two minutes

long, and fresh water was used between washes. This washing was performed in water rather than buffer in order to prevent buffer salt crystals which form abundantly on the surface if buffer is allowed to dry on the devices, rendering the sensors

effectively useless. Next, affinity-purified, polyclonal goat antibodies for human

free PSA were immobilised on the surface during a one hour incubation using an antibody concentration of 50 mg m/L.Unreacted gluteraldehyde was then quenched by immersing the chips in 50 mM solution of glycine for 30 minutes. A blocking step was performed for 15 minutes using a 1% solution of bovine serum albumin (BSA) in phosphate buffered saline (PBS) that had been filtered through a 0.2 mm pore filter. Free PSA (>98% pure, human) was then spiked into undiluted fetal bovine serum (FBS, HyClone, Thermo Scientific) at concentrations ranging from 50 fg m/L to 50 ng m/L and incubated on the devices for one hour. Control chips were incubated with FBS containing no PSA. All FBS was filtered through 0.2 mm filter prior to use. Following another 15 minute blocking step in 1% BSA, monoclonal mouse antibodies to human free PSA (epitope 1) were used as the secondary antibody in the sandwich assay and incubated on devices at a concentration of 50 mg m/L in PBS for one hour.

Both of the antibodies as well as the PSA were purchased from Meridian Life Science, Inc. (Cincinnati, OH). Magnetic nanoparticles coated in goat anti-mouse IgG antibodies

(R&D Systems, Minneapolis, MN) were used to bind to the secondary mouse antibodies. The nanoparticles measure roughly 100-150 nm in diameter, and correspondingly have

masses on the order of 1 fg. Prior to incubation with nanoparticles, a 15 minute blocking step was again performed. Finally, a 1:50 dilution of nanoparticles was prepared in the1%

BSA blocking solution and incubated on chips for 90 minutes, followed by another washing step. The chips were dried using a stream of nitrogen before loading in vacuum and measuring resonant frequencies before and after incubation with nanoparticles.[9,10]

Frequency response of resonant sensors due to the addition of nanoparticles for different PSA concentrations, demonstrating a concentration sensitivity of 50 fg m/L (P < 0.0005). The inset shows control responses observed during the tests performed at different concentrations, demonstrating consistent but slightly varying background signals due to variations in non-specific binding and environ mental conditions from day-to-day.

Fig Representive SEM images of trampoline resonators showing that the number of nanoparticals bound to devices scales with PSA concentration. Scale bar represents 1micro meter

Conclusions.

Clinically relevant concentrations of prostate specific antigen were detected from undiluted fetal bovine serum using nanomechnical trampoline resonators at concentrations ranging from 50fg m/L or 1.5fM to 1.5 nM. We also note that the flexibility of these sensors is limited only by the availability of specific biorecognition layers and functionalisation techniques. The high sensitivity of these robust resonator arrays,in addition to their small size and versatility, suggests that they will find use in many applications, including miniaturized sensors and multiplexed detection systems.

Importance for AFM

A key application of NEMS is Atomic force microscope tips. The increased sensitivity achieved by NEMS leads to smaller and more efficient sensors to detect stresses, vibrations, forces at the atomic level, and chemical signals [11]. AFM tips and other detection at the nanoscale rely heavily on NEMS. If implementation of better scanning devices becomes available, all of nanoscience could benefit from AFM tips.

Approaches to miniaturization

Two complementary approaches to fabrication of NEMS systems can be found. The top-down approach uses the traditional microfabrication methods, i.e. optical and electron beam lithography, to manufacture devices. While being limited by the resolution of these methods, it allows a large degree of control over the resulting structures. Typically, devices are fabricated from metallic thin films or etched semiconductor layers.

Bottom-up approaches, in contrast, use the chemical properties of single molecules to cause single-molecule components to (a) self-organize or self-assemble into some useful conformation, or (b) rely on positional assembly. These approaches utilize the concepts of molecular self-assembly and/or molecular recognition. This allows fabrication of much smaller structures, albeit often at the cost of limited control of the fabrication process.

A combination of these approaches may also be used, in which nanoscale molecules are integrated into a top-down framework. One such example is the carbon nanotube nanomotor.

Materials

Carbon allotropes

Rotating view of a graphite crystal (2 graphene layers).Many of the commonly used materials for NEMS technology have been carbon based, specifically carbon nanotubes and graphene. This is mainly because of the useful properties of carbon based materials which directly meet the needs of NEMS. The mechanical properties of carbon (such as large Young's modulus) are fundamental to the stability of NEMS while the metallic and semiconductor conductivities of carbon based materials allow them to function as transistors.

Both Graphene and Carbon exhibit high Young's modulus, excessively low density, low friction and large surface area. The low friction of CNTs, allow practically frictionless bearings and has thus been a huge motivation towards practical applications of CNTs as constitutive elements in NEMS, such as nanomotors, switches, and high-frequency oscillators. Carbon nanotubes and graphene's physical strength allows carbon based materials to meet higher stress demands, when common materials would normally fail and thus further support their use as a major materials in NEMS technological development.[12]

Along with the mechanical benefits of carbon based materials, the electrical properties of carbon nanotubes and graphene allow it to be used in many electrical components of NEMS. Nanotransistors have been developed for both carbon nanotubes as well as graphene . Transistors are one of the basic building blocks for all electronic devices, so by effectively developing usable transistors, carbon nanotubes and graphene are both very crucial to NEMS. Metallic carbon nanotubes have also been proposed for nanoelectronic interconnects since they can carry high current densities . This is a very useful property as wires to transfer current are another basic building block of any electrical system. Carbon nanotubes have specifically found so much use in NEMS that methods have already been discovered to connect suspended carbon nanotubes to other nanostructures. This allows carbon nanotubes to be structurally set up to make complicated nanoelectric systems. Because carbon based products can be properly controlled and act as interconnects as well as transistors, they serve as a fundamental material in the electrical components of NEMS.

Difficulties

Despite all of the useful properties of carbon nanotubes and graphene for NEMS technology, both of these products face several hindrances to their implementation. One of the main problems is carbon's response to real life environments. Carbon nanotubes exhibit a large change in electronic properties when exposed to oxygen . Similarly, other changes to the electronic and mechanical attributes of carbon based materials must fully be explored before their implementation, especially because of their high surface area which can easily react with surrounding environments. Carbon Nanotubes were also found to have varying conductivities, being either metallic or semiconducting depending on their helicity when processed [13]. Because of this, very special treatment must be given to the nanotubes during processing, in order to assure that all of the nanotubes have appropriate conductivities. Graphene also has very complicated electric conductivity properties compared to traditional semiconductors as it lacks an energy band gap and essentially changes all the rules for how electrons move through a graphene based device [9]. This means that traditional constructions of electronic devices will likely not work and completely new architectures must be designed for these new electronic devices.

Future of NEMS

Earlier than NEMS devices can actually be implemented, reasonable integrations of carbon based products must be created. The focus is currently shifting from experimental work towards practical applications and device structures that will implement and profit from the use of carbon nanotubes [6]. At this point in NEMS research, there is a general understanding of the properties of carbon nanotubes and graphene. The next challenge to overcome involves understanding all of the properties of these carbon based tools, and using the properties to make efficient and durable NEMS.

NEMS devices, if implemented into everyday technologies, could further reduce the size of modern devices and allow for better performing sensors. Carbon based materials have served as prime materials for NEMS use, because of their highlighted mechanical and electrical properties. Once NEMS interactions with outside environments are integrated with effective designs, they will likely become useful products to everyday technologies.

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