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Zinc oxide surface states can be utilized for ultra-specific detection of biomolecules. The major challenges in using ZnO for bio-sensing are attaining enhanced sensitivity and specificity. In this study, we explore the functionalization of zinc in ZnO through utilizing the thiol bond. The purpose of this study is to demonstrate that the ZnO based sensor is capable of achieving high specificity in presence of competitive surface binding through the thiol bond. The final goal is to design an ultra-specific biosensor to detect low occurring biomolecules. In this study, we have selected cortisol as a stress marker to demonstrate quantification and detection from synthetic sweat. In order to demonstrate ultra-specificity, we have used two competitive thiol based molecules binding to zinc, a linker Dithiobis succinimidyl propionate (DSP) and reducing agent of DSP, Dithiothreitol (DTT). Electrochemical impedance spectroscopy (EIS) is used to quantify the signal obtained through various ratiometric concentrations of DSP and DTT. To validate the EIS study results, inherent fluorescence studies are done by mapping changes in green emission spectrum of ZnO before and after linker functionalization. The optimal combination in terms of highest signal is identified to be of 25mM DTT and 50mM DSP. This is implemented in the experiments performed to calibrate the cortisol concentration in synthetic sweat. This study demonstrates the detection of cortisol antigen in synthetic sweat present within the physiological levels of 8 ng/mL to 140 ng/mL.
In this work, we demonstrate the label-free and ultrasensitive detection of troponin-T, cardiac biomarker using nanoporous membrane integrated on a microelectrode sensor platform. The nanoporous membrane allows for spatial confinement of the protein molecules. Antigen interaction with thiol immobilized antibody perturbs the electrical double layer. Charge perturbations are recorded as impedance change at low frequency using the principle of electrochemical impedance spectroscopy (EIS). The measured impedance change is used to quantitatively determine the concentration of troponin-T in tested sample. We have shown that sensitivity of sensor for troponin-T to be 1pg/mL. The accuracy and reliability of this sensor was tested by comparing the experimental troponin-T concentration values with a commercially available electrochemiluminescence assay measured with Roche Elecsys analyzer. Using this technique we were successful in detecting protein biomarkers in whole blood, human serum, and ionic buffers. This technology provides a robust analytical platform for rapid and sensitive detection of protein biomarkers, thus establishing this technology as an ideal candidate for biomarker screening in clinical settings.
This study demonstrates the development of a zinc oxide (ZnO) based microelectrode sensor for the ultra-sensitive detection of protein biomarkers. Our research focuses on utilizing a materials-based approach to achieve this objective by utilizing ZnO as part of our biosensor for (1) improved surface binding to enhance sensitivity and (2) creating a nanotextured surface for enhanced output signal response. Nanotextured ZnO thin films were integrated onto printed circuit boards using RF magnetron sputter deposition. Films sputtered with and without the presence of oxygen were examined for possible differences in biosensor efficacy. These fabrication conditions not only dictate the number of oxygen vacancies within the film but also regulate the amount of zinc and oxygen terminated ends occurring on the material surface. The correlation between the surface terminations of the nanotextured ZnO to its performance as a biosensor was evaluated using two cross-linker molecules, dithiobis succinimidyl propionate and (3-aminopropyl)triethoxysilane, that maintain different binding chemistries to ZnO. Qualitative and quantitative assessment of cross-linker binding was accomplished using fluorescent microscopy and fluorescent intensity measurements. Electrical impedance spectroscopy (EIS) was used as the transduction mechanism for detection of the well-established cardiac biomarker, troponin-T. Utilizing EIS with a functionalized immunoassay on the ZnO surface, troponin-T was detected as low as 10 fg/mL using ZnO films sputtered without oxygen. This enhanced detection of the cardiac biomarker can be directly attributed to 1) oxygen vacancies within the metal oxide film, 2) the nanotexturing of the sensing site surface, and 3) the ability to bind a significant amount of cross-linker molecules for immobilizing capture antibodies.
This work presents a strategy to perform ex-vivo cell-drug interaction studies through electro-kinetically assisted drug delivery system. Here, we present a novel technique to electro-kinetically control the vesicles carrying drug to deliver to pre-determined locations. In order to achieve efficient targeted drug delivery, effect of electrokinetic attractive and repulsive forces on liposomes and target cells were studied and presented. The device consists of a simple bifurcated microfluidic chamber and microelectrodes that assist in carrying the liposomes to the target location. To test the prototype, fully grown human embryonic kidney cell lines (HEK 293) and trypsin as test drug was used. External electrical signal with voltages less than of 5 V peak-to-peak (Vpp) for cells and 10 Vpp for liposomes were applied over a spectrum of frequencies to study the effect of electrokinetic forces. Through this label-free method, we were able to study loading and unloading efficiency of the drug without altering the natural properties of the liposomes and target cells. In this study, characterization and performance comparison studies for two different types of materials (HEK cells and liposomes) were performed. We were able to achieve an overall efficiency of approximately 85%. Various electrical parameters such as applied voltage, frequency and conductivity were manipulated to study the drug-cell interaction. This electrokinetic based method will be highly applicable in understanding the effect on drugs on cell populations ex vivo.
Hybrid organic/inorganic nanostructures are engineered to function as two terminal devices with enhanced functionality. The devices are the building blocks for designing hybrid organic/inorganic circuits in the nanoscale. In our work, we have demonstrated the sensing capabilities of polymer nanocomposite thin films for designing nanoweb devices towards detection of biomolecules. Biomolecules with surface charge such as troponin-T were detected on this device by interfacing them with the polymer/metal composites. The change in electrical properties due to modulation in charge transport at the crossbar junction was identified as the measured electrical signal for designing switch based sensors. Nanotextured surface offers strong charge carrier transport and hence enhances the strength of the detected signal. The antibodyantigen interactions at the junction effectively modulate the charge transfer kinetics and modify the junction characteristics due to the surface potential associated with the organic molecules. The net change in surface charge can be measured either as changes in the diode current in the two terminal configuration or as changes in the source- drain current in the three terminal configuration. Detection sensitivity in the order of pg/mL was targeted by measuring the voltammetric current response (in microamperes).
The ability to design a diagnostics platform that can achieve cellular level as well as molecular level classification of targeted biomarkers may be critical toward understanding the fundamental basis of disease initiation and proliferation in breast cancer. In this context, we have looked at breast cancer diagnostics and present the design of a biomedical microdevice for evaluating and classifying cellular samples based on their risk towards metastasis. Primary breast cancer tumors have been shown to contain heterogeneous populations of neoplastic cells. Recent studies have demonstrated that subpopulations of these cells can cooperate in the initiation of collective invasion and metastasis. The role of the sensor we present is to identify the type of cells as non-invasive/”follower” cells that do not result in metastasis or invasive “leader” cells that are thought to be responsible for metastasis, from breast cancer cell lysate samples, thus enabling more selective classification of samples, with the eventual goal of early diagnosis. The device is an electrical immunoassay that incorporates the PDGF- receptor to screen the cell lysate samples for the PGDF binding protein that is preferentially expressed in the invasive, “leader” cells. The sensor comprises of alumina nanochannel arrays integrated on to a microelectronic platform operating on the principle of electrochemical impedance spectroscopy to quantify the PGDF protein from the cell lysates.
Neurodegenerative disease is primarily characterized by protein misfolding and the resultant protein aggregation. Presence of soluble oligomeric aggregates of proteins including various Aβ and α-syn aggregate species can be correlated to the onset and progression of many neurodegenerative diseases. The ability to detect protein misfolding requires the design of a diagnostics assay the will enable molecular level probing. The use of nanoporous ceramic templates enables size based immobilization of the target proteins and by leveraging the principle of “macromolecular crowding” protein association can be mapped with a high degree of resolution. By tailoring the surface functionalization within nanoporous ceramic templates, macromolecular immobilization can be selectively controlled, which in turn significantly enhances the perturbation to the electrical double layer/. The changes to the electrical double layer are measured with a high degree of sensitivity through impedance spectroscopy.
Pre symptomatic diagnosis and distinction between Alzheimer’s and Parkinson’s diseases can be achieved by the specific detection and quantification of levels of each of these different toxic protein species in cerebrospinal fluid (CSF). Detection using highly selective morphology specific reagents in conjunction with the ultrasensitive nanoporous electronic biosensor showed the presence of different protein morphologies in human CSF samples. Detection is primarily achieved by identifying the specific association of the protein with its receptor using electrochemical impedance spectroscopy. Furthermore, we show that these morphology specific reagents can readily classify between post-mortem CSF samples from AD, PD and cognitively normal sources. These studies suggest that detection of specific oligomeric aggregate species holds great promise as sensitive biomarkers for neurodegenerative disease.
The goal of this work is to understand the role of nano-confinement in designing an inexpensive and user friendly ‘point- of- care’ (POC) protein biosensor. We used printed circuit board based gold chips and integrated them with nanoporous alumina membranes in generating high density arrays of nano scale confined spaces. We initially tested the role of a nanomembrane in achieving signal enhancement through size based confinement of proteins. As a later part of the experiment, we studied the role of pore size on achieving signal enhancement by using membranes of two different pore sizes of 100 and 200 nm. It is critical that ultralow detection of biomolecules be achieved as they have significant impact in designing diagnostics platforms for early disease diagnosis. Commercially available nano-porous membranes made out of anodized alumina were evaluated for their role in nano-confinement and enhancing sensitivity of detection. In this biosensor configuration sandwich assay, an electrical double layer is formed between a test protein (C-reactive protein) and the gold surface underneath the porous membrane. Using electrical impedance spectroscopy, the capacitance/impedance changes in the electrical double layer, was analyzed which translated to identifying the sensitivity and the linear dose response of the sensor for two specific conditions (a) with nano confinement and (b) for varying size of confined spaces
“Label-free” biomolecule sensors for detection of inflammatory cardiovascular biomarker associated with vulnerable coronary vascular plaque were designed and fabricated using micro and nano-textured polystyrene structures that functioned as sensing elements coupled with electronic measurement equipment. We demonstrated that scaling down the surface texturing from the micro to the nanoscale enhances the amplitude of the measured signal strength. We believe that the nanoscale fiber morphology provides size matched spaces for trapping and immobilizing the protein biomolecules resulting in enhanced detection and signal strength. We selected polystyrene as the model system and demonstrated the detection of human serum C-reactive protein (hs-CRP). We employed these findings in designing a platform “lab-on-a-chip” protein sensor. Comparative studies were performed on two different polystyrene textured surfaces: a polystyrene microsphere mat, and an electrospun polystyrene nanofiber matrix.
This paper describes the development of nanomonitors, which are electrical immunoassays for detection of multiple protein biomarkers. These devices are hybrid sensors with micro-fabricated electrode arrays on a silicon substrate, and integrated nanoporous alumina membranes to provide protein confinement and signal amplification. The disease biomarkers C-reactive protein and Myeloperoxidase have been detected by the nanomonitors in ultra-low concentrations. Proteins were detected in pure samples, human serum, and patient blood samples. The detection accuracy and sensitivity of the nanomonitors in patient samples was comparable to the Enzyme Linked Immunosorbent Assay (ELISA) method of protein detection. Nanomonitors provide the additional benefits of being rapid, label-free, sensitive, and cost effective, providing improvements over traditional protein detection methods, and having potential applications in disease diagnosis.
The use of herbal remedies individually or in combination with standard medicines has been used in various medical treatises for the cure of different diseases. Pumpkin is one of the well-known edible plants and has substantial medicinal properties due to the presence of unique natural edible substances. It contains several phyto-constituents belonging to the categories of alkaloids, flavonoids, and palmitic, oleic and linoleic acids. Various important medicinal properties including anti-diabetic, antioxidant, anti-carcinogenic, anti-inflammatory and others have been well documented. The purpose of the present article is to discuss various medicinal and biological potentials of pumpkin that can impart further research developments with this plant for human health benefits.
The current demand in the automobile industry is in the control of air-fuel mixture in the combustion engine of automobiles. Oxygen partial pressure can be used as an input parameter for regulating or controlling systems in order to optimize the combustion process. Our goal is to identify and optimize the material system that would potentially function as the active sensing material for such a device that monitors oxygen partial pressure in these systems. We have used thin film samaria doped ceria (SDC) as the sensing material for the sensor operation, exploiting the fact that at high temperatures, oxygen vacancies generated due to samarium doping act as conducting medium for oxygen ions which hop through the vacancies from one side to the other contributing to an electrical signal. We have recently established that 6 atom % Sm doping in ceria films has optimum conductivity. Based on this observation, we have studied the variation in the overall conductivity of 6 atom % samaria doped ceria thin films as a function of thickness in the range of 50 nm to 300 nm at a fixed bias voltage of 2 volts. A direct proportionality in the increase in the overall conductivity is observed with the increase in sensing film thickness. For a range of oxygen pressure values from 0.001 Torr to 100 Torr, a tolerable hysteresis error, good dynamic response and a response time of less than 10 seconds was observed.
The paper describes the fabrication and characterization of an ionic junction nanodevice as a biosensor using surfactant coated single walled carbon nanotubes (SWCNT's) via microcontact printing and its application in detecting standard protein biomolecules ( biotin-avidin). Intrinsic semiconducting SWCNT's are doped with anionic and cationic surfactant molecules respectively. Using double patterning process, these ionically doped anionic and cationic semiconducting SWCNT's are alternatively symmetrically patterned in a parallel array to form crossbar junctions onto base microelectrode arrays using flexible polymeric poly-dimethylsiloxane (PDMS) stamps. Parallel alignment of SWCNT's is achieved, due to transfer of the inked SWCNT's from the PDMS relief structure onto the microelectrode array. Base microcontacts on the microelectrode array serve as a platform for measuring electrical characteristics that get modulated due to the biomolecule binding. Functionality of the nanodevice is demonstrated by measuring impedance changes due to biomolecule binding. The modulation of the electrical behavior indicates the existence of potential for using ionically doped nanomaterial systems in fabricating functional building blocks for biosensors.
Changes in protein glycosylation have great potential as markers for the early diagnosis of cancer and other diseases. The current analytical tools for the analysis of glycan structures need expensive instrumentation, advanced expertise, is time consuming and therefore not practical for routine screening of glycan biomarkers from human samples in a clinical setting.
We are developing a novel ultrasensitive diagnostic platform called ‘NanoMonitor’ to enable rapid label-free glycosylation analysis. The technology is based on electrochemical impedance spectroscopy where capacitance changes are measured at the electrical double layer interface as a result of interaction of two molecules.
The NanoMonitor platform consists of a printed circuit board with array of electrodes forming multiple sensor spots. Each sensor spot is overlaid with a nanoporous alumina membrane that forms a high density of nanowells. Lectins, proteins that bind to and recognize specific glycan structures, are conjugated to the surface of nanowells. When specific glycoproteins from a test sample bind to lectins in the nanowells, it produces a perturbation to the electrical double layer at the solid/liquid interface at the base of each nanowell. This perturbation results in a change in the impedance of the double layer which is dominated by the capacitance changes within the electrical double layer.
The nanoscale confinement or crowding of biological macromolecules within the nanowells is likely to enhance signals from the interaction of glycoproteins with the lectins leading to a high sensitivity of detection with the NanoMonitor as compared to other electrochemical techniques.
Using a panel of lectins, we were able to detect subtle changes in the glycosylation of fetuin protein as well as differentiate glycoproteins from normal versus cancerous cells. Our results indicate that NanoMonitor can be used as a cost-effective miniature electronic biosensor for the detection of glycan biomarkers.
Current trends in sensing and diagnostics is towards developing hybrid devices that incorporate nanomaterial for enhancing device performance. These devices and systems have a broad impact ranging from personalized medicine in health care, environmental sensing and building multifunctional sensors for military applications. The overarching objective of the research work is to develop a new class of portable, bio-analytical tools with improved functionality and performance capabilities by utilizing the electrical effects on cellular and sub cellular species in micro and nanoscale domains.
There are two key ideas underlying this research work. The first is to design and manufacture structures comprising of nanoscale-confined spaces integrated on to multi-scale architecture platforms. This model architecture has been engineered to harness the principle of macromolecular crowding for biomolecule binding and detection by monitoring perturbations in the electrical bi-layer in tailored nanoscale confined spaces. Enhanced performance metrics in biomolecule detection have been demonstrated in developing electrical immunoassays. We have demonstrated picogram/ml sensitivity in detection of specific cardiovascular disease biomarkers, cancer biomarkers from human serum samples with a dynamic range of response varying from pg/ml to g/ml and response time within 120 seconds.
Pt, Ir, Au and few other precious metals have highly conducive electrical and chemical properties; hence have been widely used in pH sensors and bimolecular sensing applications. The chief objective of this research is to highlight and demonstrate the advantages that Iridium Oxide (IrOx) nanowires offer over these competing metals in improving the performance metrics of biomolecular sensing. Iridium oxide has very good conductivity and very high charge storing capacity, and hence has an ability to detect very small changes in the surface charge. Nanowires have an ideal morphology to crowd protein molecules and highly increase the surface area of interaction. Higher area of interaction along with iridium oxide's high intrinsic physical adsorption rate, strongly enhance the rate of immobilization of biomolecules and hence enabling high sensitivity detection. Inflammatory protein, C-Reactive protein (CRP) that is a biomarker for cardiovascular disease was used as the model biomolecule for this study.
The immobilization of biomolecules on a solid substrate and their localization in “small” regions are major requirements for a variety of biomedical diagnostic applications, where rapid and accurate identification of multiple biomolecules is essential. In this specific application we have fabricated nanomitors for identifying specific protein biomarkers based on the electrical detection of antibody-antigen binding events.
The nanomonitor, lab-on-a-chip device technology is based on electrical detection of protein biomarkers. It is based on developing high density, low volume multi-well plate devices. The scientific core of this technology lies in integrating nanomaterial with micro fabricated chip platforms and exploiting the improve surface area to volume to improve the detection.
The devices that have been developed utilize electrical detection mechanisms where capacitance and conductance changes due to protein binding are used as “signatures” for biomarker profiling. In comparison to optical methods, the electrical detection technique is non-invasive as well as a label free. The signal acquisition is simple and it uses the existing data acquisition and signal analysis methods
The paper presents an evaluation of the feasibility of developing ionic surfactant coated single walled carbon nanotube (SWCNTs) (P-N) junction clusters via microcontact printing using intrinsic semi conducting SWCNTs. These SWCNTs are doped with anionic and cationic surfactant molecules respectively, thereby altering the Fermi energy levels of and its electrical properties. Two types of surfactants were used for doping the SWCNTs to develop extrinsically doped P and N type SWCNTs. Sodium dodecyl sulfate (SDS) having Na+ positive ionic charge (anions) and Cetyl trimethylammonium bromide (CTAB), having Br- negative ionic charge (cations) on its hydrophilic ends have been used to generate anionic SWCNTs (P type) and cationic SWCNTs( N- type respectively.
Using, dual level patterning process, these extrinsically doped anionic and cationic semiconducting SWCNTs clusters are alternatively symmetrically patterned in a parallel array to form crossbar P-N junctions onto a standard microfabricated platform using flexible polymeric poly-dimethylsiloxane (PDMS) stamps. Ink-based transfer of the nanomaterial from the relief structures achieves parallel alignment of SWCNTs clusters. The electrical device characterization is achieved by measuring I-V characteristics from the base micro fabricated platform.
Functionality of the nanodevice is demonstrated by studying the rectifying current – voltage (I-V) characteristics that shows promise towards the formation of a junction diode array, which can be used for integrating complex logic devices for high-end applications such as memory module and addressable logic. Lastly, we believe that the chemical modulation method and microcontact printing techniques will have a wide scope for development of nanomaterial-based devices.
The objective of this research is to develop a “point-of-care” device for early disease diagnosis through protein biomarker characterization. Here we present label-free, high sensitivity detection of proteins with the use of electrical immunoassays that we call Nanomonitors. The basis of the detection principle lies in the formation of an electrical double layer and its perturbations caused by proteins trapped in a nanoporous alumina membrane over a microelectrode array platform. High sensitivity and rapid detection of two inflammatory biomarkers, C-reactive protein (CRP) and Myeloperoxidase (MPO) in pure and clinical samples through label-free electrical detection were achieved. The performance metrics achieved by this device makes it suitable as a “lab-on-a-chip” device for protein biomarker profiling and hence early disease diagnosis.