Spatial localization of signals is commonplace within cells and allows for a variety of integral biological processes, including cell migration and polarization in development, neural synapse strengthening in learning, and correct cell division to avoid cancer development and progression. Despite the importance, few general tools have been developed to understand and probe spatial localization. We present a technique that translates the centimeter scale motions of an external magnet into nanometer scale motions of superparamagnetic nanoparticles internalized within cells growing on specially patterned “nano-active” substrates. In this way, localization of mechanical forces, or localization of nanoparticle-bound biomolecules can be controlled in real time.

This talk is aimed at presenting novel solutions developed recently by the author’s group for many neurological disorders including Parkinson’s disease, Alzheimer’s disease, depression, anxiety, sleep apnea and sleep disorders using the fundamental research and developments in nanotechnologies and wireless sensor network. Point-of-care (POC) diagnostics promises to bring diagnostic testing out of the laboratory directly to patients and the general public wherever they may be. The key to POC diagnostics is capable of bringing immediate answers so that health care professionals can make rapid and accurate diagnosis of disease so as to ensure the effectiveness of therapy and early detection for preventive therapy. Selected movies illustrating the applications of both invasive and non-invasive wireless nanosensor systems to patients and surgical procedures will be shown at the talk.

Biosensor detection process involves binding between biomolecules in a solution and a functionalized sensor surface. These sensors are time and cost efficient, sensitive, and enable new applications in medicine, drug design, and environmental monitoring. In literatures, various biosensor designs have been proposed, such as planar electrodes, nanowire, and nanospheres for different applications. However, to fully realize the potentials of these biosensors for biomarker/nanoparticle detection, several challenges must be addressed. In particular, ultra-sensitive biosensors are needed for detection of ultra-low concentration biomarkers such as cancer markers for early disease detection. The goal of this paper is to understand the diffusion process of biomarkers in a liquid solution and the binding with nanosensor surface through a stochastic particle model.

Nanochips ® cartridges (Fig 1) are disposable panels with 400 micro arrays (Fig 2) that can be independently used as test sites for various assays like genetic marker. Each site (Fig 3) is a permeation layer coated electrode with 80 μ diameter and 120 μ pitch. Permeation or “perm” layer is a thin film of a proprietary hydrogel material over the proprietary chip design. Perm layers were deposited on the electrodes using spin coating process with a proprietary solution. Performance of the cartridge depended on the quality and thickness of the permeation layer over these 400 electrodes. In this process one millimeter deep tear shaped well was constructed from the ceramic base to which 20×20 array of silicon chip were attached. These wells filled with 180 μl proprietary solution and spun at fixed 1200 RPM for 20 seconds. Process was repeated three times at room temperature in a clean room. Post process treatment included 30 minutes in dry incubator, wash in Milli Q water, and finally, dry at room temperature. Quality of the 1,500 nm thick permeation layer was so demanding that more than half of the cartridges were rejected due to poor quality of the perm layer. Major causes of rejection were bubbles, high SD (Standard Deviation), and thickness (too thick or too thin) of the layer. To understand the problem focus was given to both solution making and spin coating process. Basic hypothesis was that the film thickness was based on viscosity of solution and subsequent evaporation process. Figs 4–6 showed the details of spin coating process for developing a heuristic model. Since viscosity depended strongly on the temperature and time during a chemical reaction, a viscosity profile was developed for the solution during the reaction. From the viscosity curve (Fig. 7) it was established that 75 minute at 50° C was not enough to complete the reaction as was initially thought. The time-Viscosity curve reached the plateau after 150 minutes! So, it was necessary to continue the reaction for 75 more minutes to complete the reaction. This explained a major reason (bubble forming) in the present process. Viscosity of the solution depended on a number of other factors like dispensed volume, temperature of the spinneret, time to dispense and/or in the spinneret, etc. A systematic study on these variables led to an empirical equation of the following form: H f = H f 0 + A * ( τ e / V d ) * η f * ( T c − T 0 ) n Where H f = Predicted Average Thickness in nm. H f0 is minimum average thickness in nm. T, V, and τ are various temperature, dispensed volume, and time parameters. A and n are curve fitting constants for experimental set-ups. The best of part of this modeling was its ability not only to predict the thickness of the film, rather its ability to control the thickness of the film in real time for a given solution. Above equation allowed appropriate dispensing volume and time to be kept in the well of the chip before spinning for a given solution with a specific viscosity. A tabular form was given to the operator who matched the information to get a specific film thickness. This model helped dropped the rejection rate to less than 10% from more than 50%. Operators were able to control the thickness of the film within 1500 nm +/− 300 nm, as demanded by the Spec. The model further allowed to target, rather control, the film thickness. We were also able to make films as thin as 800 nm or as thick as 1,500 nm with +/− 200 nm variation from the Table developed from the empirical equation. Using the assumption that viscosity plays the most important role in our spin coating process and constructing a corresponding evaporative model, we were able to identify a major shortcoming of an existing process to develop submicron thick permeation layer. Existing process was resulting in more than 50% rejection of an expensive critical component. An empirical model of spin coating process was developed to predict the film thickness within hundreds of nanometers. This dramatically improved the yield to more than 90% from less than 50%. The model allowed to correct the process in real time and allowed targeting the film thickness anywhere around one micron with few hundred nanometer accuracy.

We present a new biomechanical approach to measure nanoscale platelet contractile forces, which play an important role in the regulation of hemostasis and thrombosis. Previous studies have indicated that platelets generate contractile forces through actin-myosin interactions that lead to clot retraction and stability. If platelets are unable to generate forces, then the clots they form are loosely-bound and may detach to cause an embolism. Likewise, a higher propensity toward contractility by platelets may cause excessive clot formation in arteries and block blood flow.

In our early work, cellulose has been discovered as a smart material. This newly discovered material is termed as electro-active paper (EAPap) that has merits in terms of lightweight, flexible, dryness, biodegradable, biocompatible, easy to chemically modify and cheap [1]. The actuation principle of cellulose EAPap actuator is known to be a combination of piezoelectric effect and ion migration effect. Since this new material is biodegradable and biocompatible, there are a lot of possible biomedical applications. This paper presents bacterial cellulose composites made by blending chitosan, poly(ethylene glycol) and gelatin for potential biomedical application of tissue engineering scaffold and would dressing material. The bacterial cellulose composites were successfully prepared by immersing wet bacterial cellulose pellicle in to chitosan, PEG or gelatin solutions followed by freeze-drying. The products look like a foam structure. Cell adhesion studies for these composites were carried out using 3T3 fibroblast cells. They showed much better biocompatibility than pure bacterial cellulose. Also, the concept of smart bandage is explained, which can come up with medical treatment layer of cellulose, sensing layer, antenna layer and integration of these layers. Issues in developing smart bandage are addressed in this paper.

Based on the first experiment on Differential Femto Oximetry (Paper 13270), we conducted a computer simulated study of the feasibility of conceptual design for our noninvasive malignancy probe, Oncosensor, to diagnose hypoxia of malignancy M = −0.90, measured by pO 2 — which correspond to volume averaged hypoxia M ′ = −0.09 — in 1cm, 3 cm and 5 cm DIA tumors embedded in the middle of a 10 cm DIA breast. M ′ is further masked by background γ’s from the in vivo tissue by factor x = 4.4–7 for subcutaneous and central tumor, respectively, to apparent M ″ = M ′ /X which, in turn, renders hypoxia non-diagnosable for 1 cm tumors; marginally so for 3 cm ones with specificity S = 75%, and fully diagnosable with S = 95% in 5 cm ones. To diagnose 1–3 cm and smaller tumors, we propose to enhance M ″ by a factor of ≈ 3 by replacing air breathing with that of Carbogen (O 2 95%, CO2 5%). With carbogen breathing, simulations predict hypoxia detection in 1 cm subcutaneous tumor with S = 68%, and in 3 cm ones with S = 95–99.9%. Carbogen renders possible 2 additional diagnostic tests for redundancy. Significant improvements of the above measurement accuracies are projected. Oncosensor will be tested in vivo with R3230 tumors in Fischer rats at UCI’s Center for Functional Onco-Imaging. Oncosensor requires imaging guidance.

The enterovirus 71 (EV71) has threatened Taiwan for more than ten years. Since traditional diagnostic methods are complicated, time consuming, and high-qualified personnel required. Therefore, a new detection process is highly desired. In this study, a high sensitive PC-based electrochemical analyzing system with a functionalized nano-gold modified immunological electrode are developed to detect EV71. Immobilizing specific EV71 polyclone antibodies, which is developed by center for disease control (CDC) Taiwan, onto nano gold of sensing electrode, the affinity interaction of the immobilized antibody with the specific antigen is identified quickly by electrochemical impedance spectrum (EIS) within 20 minutes. The detection limit of this EIS analysis was as low as 50 copy per ml (∼sub-atto molar). In summary, a biosensor and analyzing system based on EIS has been developed to identify EV71 with efficiency, high sensitivity and specificity.

A critical challenge in the field of medicine is to develop a low cost sensor competent of detecting specific bacterial pathogens via a precise deoxyribonucleic acid (DNA) sequence. In order to identify such biological agents in a patient’s blood or other bodily fluids at the onset of infection, detection of specific pathogen genomic DNA is considered a reliable approach. Current techniques involving multiplex DNA/RNA detection arrays or immunoassays [1] require cumbersome sample preparation, aggressive nucleic acid amplification protocols and must be operated by trained personnel. To overcome the aforementioned obstacles, a time-dependent dielectrophoretic force driven sensor consisting of nanostructured tip is being developed.

Tuberculosis (TB) is one of the most widely spread diseases. In 2006, 9.2 million new TB cases were reported with 1.7 million victims [1]. To diagnose TB, Mycobacterium tuberculosis (MTB) is identified in clinical samples. The challenge of TB diagnostics is high-performance screening conducted by nontrained personnel. Currently, nucleic acid testing with target-amplification strategy such as polymerase chain reaction (PCR) is available for detection of TB. However, this entails cumbersome procedures run by skilled operators with expensive instrumentation and reagents. To overcome these challenges, this paper presents a nanotip sensor to diagnose TB rapidly without target-amplification. The proposed methodology uses a nanostructured tip as a biosensor to detect target analytes. The novelty of this approach is in the superior concentration and detection mechanisms of nucleic acids on the terminal end of a nanotip using an alternating current (AC) electric field, specific chemical binding, and capillary action. Confirmatory identification of MTB is achieved by detecting MTB strains on a nanostructured tip through DNA hybridization. In this paper, the working principle is presented with the demonstration of amplification-free detection of MTB genomic DNA using the nanotip sensor. The performance of the tip sensor is characterized.

Current efforts in medical diagnostic technology focus toward developing biological sensors with the capacity for detecting trace quantities of specified organic molecules. In this study, metallic nanoparticles were investigated for the development of field-enhanced chemical and biological detection devices with the capacity to achieve single-molecule level detection resulting from surface enhanced Raman scattering (SERS) associated with closely spaced noble metal nanostructures.[1, 2] Localized surface plasmon resonance (LSPR) sensors likewise benefit from the incorporation of ordered metal nanoparticles on surfaces, providing increased shift in minimum of reflectivity with biological binding event (figure 1).[3]

Our previous studies have shown that the flagellated nanomotors combined with the nanometer-sized chain of magnetosomes of a single Magnetotactic Bacterium (MTB) can be used as an effective integrated propulsion and steering system for microscale nanorobots. In this case, magnetotaxis has been exploited to control the swimming direction of the flagellated bacteria. This was done by inducing a directional torque on the chain of magnetosomes embedded in each bacterial cell. This approach allowed us to control swarms of flagellated bacteria of type MC-1 to accomplish relatively complex computer coordinated tasks such as micro-assemblies and drug deliveries, to name but only two examples. But the motion of each cell can also be influenced by other sensory means besides magnetotaxis, and includes chemotaxis, phototaxis, and aerotaxis. Here we show examples of MC-1 flagellated bacteria being controlled by magnetotaxis or aerotaxis. It is then demonstrated that these flagellated bacteria can not only provide an effective propulsion and steering system for future bio-nanorobots but also various sensory means capable of influencing their motions and swarm formations.

Many upcoming applications, such as nanoelectronic circuitry, single-molecule based chips, nanofluidics, chemical sensors, and fuel cells, require large arrays of nanochannels and nanowires. To commercialize such nanostructured devices, a high resolution and high throughput patterning method is essential. For this purpose, we developed the shadow edge lithography (SEL) as a wafer-scale, high-throughput nanomanufacturing method [1]. In the proposed method, the shadow effect in the high-vacuum evaporation was theoretically analyzed to predict the geometric distribution of the nanoscale patterns [2]. In experiment, nanoscale patterns were created by the shadow of aluminum (Al) edges that were prepatterned using a conventional microfabrication method.

Due to their unique structural and magnetic properties, magnetic nanotubes could be used in the field of neuroscience. In this study, hematite and maghemite nanotubes were synthesized and characterized. These magnetic nanotubes with coupled proteins such as albumin or laminin were used to investigate the interaction of nanotubes and their influence on somatosensory neurons from the dorsal root ganglion of rat. Our results indicated differential effects of magnetic nanotubes on neuronal growth based on the nanomaterial.

Gastroesophageal reflux disease (GERD) is recognized the primary risk factor associated with esophageal cancers. Therefore, monitoring GERD symptoms accurately is important for early diagnosis of such cancers. In this work, interdigitated impedance sensing electrodes and nanofabricated IrOx-based pH sensing electrodes were made on the flexible substrates that can be easily embedded into an implantable device. The dual sensor electrodes were integrated into a batteryless wireless capsule packaged with biocompatible material for implant applications. The proposed sensing system has been tested with stimulated solutions of different pH values recording modulated sensor data in terms of frequency shifts to verify its performance. The experimental results showed that the impedance electrodes responded to ion content variations and the pH electrodes identified the pH values of various pH solutions. Our sensing system has demonstrated the ability to detect gastroesophageal reflux activities more accurately, which could help doctors to provide precise treatment methods, consequentially lowering the risks of esophageal cancer development.

Electro-active polymer working in aqueous medium has short response time and small power consumption. Polypyrrole is one of such electro-active polymers. Due to its stability, incorruptibility and micromachining compatibility, polypyrrole plays an important role in developing micro/nano-actuators for biological and chemical applications. This paper presents a flexible and reusable polypyrrole nano-valve array for biomedical applications. The nano-valves are formed by depositing polypyrrole on the anodic aluminum oxide (AAO) film by a novel method to ensure the integrity of the AAO film. The valves are actuated through the oxidation and reduction of the polypyrrole. The oxidation state of the polypyrrole makes sodium ions leaving the polypyrrole and hence contracts the polypyrrole. So the gold/polypyrrole bilayer was bended and the valves blocked. Conversely, the valve is opened as the reduction state. By controlling the open/close time with constant voltage, the diffusive quantity of the nano-valves can be easily changed.

This paper describes a wireless point-of-care patient monitoring system to monitor 3 channels of biopotential signals using a wireless sensor unit, a wireless receiver unit, and a monitoring unit. The wireless sensor unit transmits signals with Zigbee, and the wireless receiver unit which has both Zigbee and Wi-Fi transceivers receives the signals from the sensor unit and transmits the signals to the monitoring unit with Zigbee and Wi-Fi, respectively. By using both Zigbee and Wi-Fi, the wireless sensor system can achieve low power consumption and wide range coverage. The features of the system are presented, as well as biopotential monitoring results.

A compact piezoresistive microcantilever platform integrated by MEMS technique provides a convenient and reliable approach for biochemical detection. In contrast to the conventional double free-standing piezoresistive cantilever beams of heterogeneous sensing surfaces, a single free-standing piezoresistive microcantilever sensor was first proposed with the elimination of interference of chemical effect. The single beam piezoresistive sensor which is temperature-sensitive was well controlled within ±0.2°C by introducing the novel method of self elimination of thermal effect. This new approach maintains device compactness with no additional use of bulky temperature-controlled apparatus, and significantly reduces noises of temperature coefficient of resistance (TCR) and bimorph effect. The C-reactive protein (CRP) detection of the microcantilever biosensor with self elimination of thermal effect was verified with the concentration of 100 μg/mL in a room-temperature environment.

This article shows that the added mass due to fluid structure interaction significantly affects the vibrational dynamics of cilia-based devices. Our main contribution is to show that such damping effects cannot explain the substantial reduction in the resonant vibrational frequency of the cilia operating in liquid when compared to the natural frequency of the cilia in air. It is shown that an added-mass approach (that accounts for the inertial loading of the fluid) can explain this reduction in the resonant vibrational frequency when operating the cantilever-type devices in liquids. Additionally, it is shown that the added-mass effect can explain why the cilia-vibration amplitude is not substantially reduced in a liquid by the hydrodynamic drag force. Thus, this article shows the need to model the added-mass effect, both, theoretically and by using experimental results.

Microcantilever-based biosensors are rapidly becoming an enabling sensing technology for a variety of label-free biological applications due to their wide applicability, versatility and low cost. It is thus imperative for us to reveal the physical origin of adsorption-induced deformation, and to further analyze its implication of microscopic mechanisms on macroscopic deformation. In the paper, we study adsorption-induced surface stresses and microcantilever motion in alkanethiolate SAMs on Au surface. We develop a multiscale method that can analyze deformation of micro-cantilever beam subjected to bio-adsorption mechanisms calculated by ab-initio simulation and classical molecular dynamics. The adsorption mechanisms of different SAMs adsorbed on Au(111) surface, in the dry and liquid phase, are studied by ab-initio simulation and the adsorption-induced stresses are calculated through the multiscale method. The results give insight into the atomic forces and positions that play a key role in producing adsorption-induced surface stresses and resultant mechanical bending of microcantilevers.