LNBD

Publications

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules

Published: December 2016

Authors: Nakhleh, K. M.; Amal, H.; Jeries, R.; Broza, Y. Y.; Abud-Hawa, M.; Gharra, A.; Ivgi, H.; Khatib, S.; Badarneh, S.; Har-Shai, L.; Glass-Marmor, L.; Lejbkowicz, I.; Miller, A.; Badarny, S.; Winer, R.; Finberg, J.; Cohen-Kaminsky, S.; Perros, F.; Montani, D.; Girerd, B.; Garcia, G.; Simonneau, G.; Nakhoul, F.; Baram, S.; Salim, R.; Hakim, M.; Gruber, M.; Ronen, O.; Marshak, T.; Doweck, I.; Nativ, O.; Bahouth, Z.; Shi, D. Y.; Zhang, W.; Hua, Q.L.; Pan, Y.Y.; Tao, L.; Liu, H.; Karban, A.; Koifman, E.; Rainis, T.; Skapars, R.; Sivins, A.; Ancans, G.; Liepniece-Karele, I.; Kikuste, I.; Lasina, I.; Tolmanis, I.; Johnson, D.; Millstone, S.Z.; Fulton, J.; Wells, J.W.; Wilf, L.H.; Humbert, M.; Leja, M.; Peled, N.; Haick, H.

Years: 2016

Published in: ACS Nano., DOI: 10.1021/acsnano.6b04930

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

Programmed Nanoparticles for Tailoring the Detection of Inflammatory Bowel Diseases and Irritable Bowel Syndrome Disease via Breathprint

Published: September 2016

Authors: Karban, A.; Nakhleh, K. M.; Cancilla, J.C.; Vishinkin, R.; Rainis, T.; Koifman, E.; Jeries, R.; Ivgi, H.; Torrecilla, J.S.; Haick, H.

Years: 2016

Published in: Adv. Healthc. Mater., 5 (18), 2339-2344

Chemical sensors based on programmable molecularly modified gold nanoparticles are tailored for the detection and discrimination between the breathprint of irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The sensors are examined in both lab- and real-world clinical conditions. The results reveal a discriminative power accuracy of 81% between IBD and IBS and 75% between Crohn’s and Colitis states.

Printing Ultrasensitive Artificially Intelligent Sensors Array with a Single Self-Propelled Droplet Containing Nanoparticles

Published: July 2016

Authors: Homede, E.; Abo-Jabal, M.; Ionescu, R.; Haick, H.

Years: 2016

Published in: Adv. Func. Mater., 26 (35), 6359-6370

The fabrication and implementation of artificially intelligent sensor arrays has faced serious technical and/or cost-effectiveness challenges. Here, a new printing method is presented to produce a fully functional array of sensors based on monolayer-capped gold nanoparticles. The proposed printing technique is based on the so-called self-propelled antipinning ink droplet, from which evaporative deposition takes place along the path of motion. By applying actuating forces, different deposition line patterns with different thicknesses and morphology from a single droplet are generated. The functionality of the produced sensors is demonstrated by their ability to detect different representative volatile organic compounds (VOCs) belonging to different chemical families, including alcohols, alkanes, ethers, and aromatics, and under extremely different humidity levels resembling those encountered in real-world conditions. The results show that the sensors exhibit ultrasensitive sensing features, with an ability to detect and differentiate between different VOCs at low ppb levels. Additionally, the results show that the sensors are able to accurately predict VOC concentrations, viz. enable quantification capabilities, while nevertheless being inexpensive, do not need complicated and expensive printing equipment and prepatterning processes, allow low voltage operation, and provide a platform for multifunctional applications.

Silicon Nanowire Sensors Enable Diagnosis of Patients via Exhaled Breath

Published: July 2016

Authors: Shehada, N.; Cancilla, J.C.; Torrecilla, J.S.; Pariente, E.S.; Brönstrup, G.; Christiansen, S.; Johnson, D.W.; Leja, M.; Davies, M.; Liran, O.; Peled, N.; Haick, H.

Years: 2016

Published in: ACS Nano., 10, 7047-7057

Two of the biggest challenges in medicine today are the need to detect diseases in a noninvasive manner and to differentiate between patients using a single diagnostic tool. The current study targets these two challenges by developing a molecularly modified silicon nanowire field effect transistor (SiNW FET) and showing its use in the detection and classification of many disease breathprints (lung cancer, gastric cancer, asthma, and chronic obstructive pulmonary disease). The fabricated SiNW FETs are characterized and optimized based on a training set that correlate their sensitivity and selectivity toward volatile organic compounds (VOCs) linked with the various disease breathprints. The best sensors obtained in the training set are then examined under real-world clinical conditions, using breath samples from 374 subjects. Analysis of the clinical samples show that the optimized SiNW FETs can detect and discriminate between almost all binary comparisons of the diseases under examination with >80% accuracy. Overall, this approach has the potential to support detection of many diseases in a direct harmless way, which can reassure patients and prevent numerous unpleasant investigations.

Analysis of the Effects of Microbiome-Related Confounding Factors on the Reproducibility of the Volatolomic Test

Published: June 2016

Authors: Leja, M.; Amal, H.; Lasina, I.; Skapars, R.; Sivins, A.; Ancans, G.; Tolmanis, I.; Vanags, A.; Kupcinskas, J.; Ramonaite, R.; Khatib, S.; Bdarneh, S.; Natour, R.; Ashkar, A.; Haick, H.

Years: 2016

Published in: J. Breath Res., 10, 037101

Volatile organic compound (VOC) testing in breath has potential in gastric cancer (GC) detection. Our objective was to assess the reproducibility of VOCs in GC, and the effects of conditions modifying gut microbiome on the test results. Ten patients with GC were sampled for VOC over three consecutive days; 17 patients were sampled before and after H. pylori eradication therapy combined with a yeast probiotic; 61 patients were sampled before and after bowel cleansing (interventions affecting the microbiome). The samples were analyzed by: (1) gas chromatography linked to mass spectrometry (GC-MS), applying the non-parametric Wilcoxon test (level of significance p  <  0.05); (2) by cross-reactive nanoarrays combined with pattern recognition. Discriminant function analysis (DFA) was used to build the classification models; and leave-one-out cross-validation analysis was used to classify the findings. Exhaled VOCs profiles were stable for GC patients over a three day period. Alpha pinene (p  =  0.028) and ethyl acetate (p  =  0.030) increased after the antibiotic containing eradication regimen; acetone (p  =  0.0001) increased following bowel cleansing prior to colonoscopy. We further hypothesize that S. boulardii given with the standard eradication regimen to re-establish the gut microbiome was the source for long-term ethyl acetate production. Differences between the initial and the follow-up sample were also revealed in the DFA analysis of the sensor data. VOC measurement results are well-reproducible in GC patients indicating a useful basis for potential disease diagnostics. However, interventions with a potential effect on the gut microbiome may have an effect upon the VOC results, and therefore should be considered for diagnostic accuracy.

Self-Healable Sensors Based Nanoparticles for Detecting Physiological Markers via Skin and Breath: Toward Disease Prevention via Wearable Devices

Published: June 2016

Authors: Jin, H.; Huynh, T. P.; Haick, H.

Years: 2016

Published in: Nano Lett., 16 (7), 4194–4202

Flexible and wearable electronic sensors are useful for the early diagnosis and monitoring of an individual’s health state. Sampling of volatile organic compounds (VOCs) derived from human breath/skin or monitoring abrupt changes in heart-beat/breath rate should allow noninvasive monitoring of disease states at an early stage. Nevertheless, for many reported wearable sensing devices, interaction with the human body leads incidentally to unavoidable scratches and/or mechanical cuts and bring about malfunction of these devices. We now offer proof-of-concept of nanoparticle-based flexible sensor arrays with fascinating self-healing abilities. By integrating a self-healable polymer substrate with 5 kinds of functionalized gold nanoparticle films, a sensor array gives a fast self-healing (<3 h) and attractive healing efficiency in both the substrate and sensing films. The proposed platform was used in sensing pressure variation and 11 kinds of VOCs. The sensor array had satisfactory sensitivity, a low detection limit, and promising discrimination features in monitoring both of VOCs and pressure variation, even after full healing. These results presage a new type of smart sensing device, with a desirable performance in the possible detection and/or clinical application for a number of different purposes.

UV Regulation of Non-Equilibrated Electrochemical Reaction for Detecting Aromatic Volatile Organic Compounds

Published: June 2016

Authors: Jin, H.; Haick, H.

Years: 2016

Published in: Sensors and Actuators, B 237, 30-40

Analysis of aromatic volatile organic compounds (VOCs) by gas sensors is of utmost important for envi-ronmental monitoring and human health. Nevertheless, most of the reported sensors suffer the problemof undesirable detection limit & poor performance in high humid conditions. We have studied the impactof UV illumination on non-equilibrium electrochemical reactions. Such a principle was applied to yttria-stabilized zirconia-based gas sensors, which have been used in many practical applications. Typically,2 fold increase in the sensing magnitude and sensitivity was achieved with UV illumination. With thecontribution of UV light, the sensor also maintains its high-performance even at relative low operatingtemperatures. Besides, the performance of the sensor was hardly affected by a change in humidity evenwithout upon the UV illumination. These results disclose a new type of sensing principle based on thesolid-state sensing device, with desirable performance for a variety of possible detection and/or clinic applications.

Cancerous Glucose Metabolism in Lung Cancer—Evidence from Exhaled Breath Analysis

Published: June 2016

Authors: Feinberg, T.; Alkoby-Meshulam, L.; Herbig, J.; Cancilla, J.C.; Torrecilla, J.S.; Gai-Mor, N.; Bar, J.; Ilouze, M.; Haick, H.; Peled, N.

Years: 2016

Published in: J. Breath Res., 7, 10(2), 1-8

Cancer cells prefer hyperglycolysis versus oxidative phosphorylation, even in the presence of oxygen. This phenomenon is used through the FDG-PET scans, and may affect the exhaled volatile signature. This study investigates the volatile signature in lung cancer (LC) before and after an oral glucose tolerance test (OGTT) to determine if tumor cells’ hyperglycolysis would affect the volatile signature. Blood glucose levels and exhaled breath samples were analyzed before the OGTT, and 90 min after, in both LC patients and controls. The volatile signature was measured by proton transfer reaction mass spectrometry (PTR-MS). Twenty-two LC patients (age 66.6  ±  12.7) with adenocarcinoma (n  =  14), squamous (n  =  6), small cell carcinoma (n  =  2), and twenty-one controls (age 54.4  ±  13.7; 10 non-smokers and 11 smokers) were included. All LC patients showed a hyperglycolytic state in their FDG-PET scans. Both baseline and post OGTT volatile signatures discriminate between the groups. The OGTT has a minimal effect in LC (a decrease in m/z 54 by 39%, p v  =  0.0499); whereas in the control group, five masses (m/z 64, 87,88, 142 and 161) changed by  -13%, -49%, -40% and  -29% and 46% respectively. To conclude, OGTT has a minimal effect on the VOC signature in LC patients, where a hyperglycolytic state already exists. In contrast, in the control group the OGTT has a profound effect in which induced hyperglycolysis significantly changed the VOC pattern. We hypothesized that a ceiling effect in cancerous patients is responsible for this discrepancy.

A Highly Sensitive Diketopyrrolopyrrole-Based Ambipolar Transistor for Selective Detection and Discrimination of Xylene Isomers

Published: June 2016

Authors: Wang, B.; Huynh, T. P.; Wu, W.; Hayek, N.; Do, T.T.; Cancilla, J.C.; Torrecilla, J.S.; Nahid, M.M.; Colwell, M.M.; Gazit, O.M.; Puniredd, S. R.; McNeill, C.R.; Sonar, P.; Haick, H.

Years: 2016

Published in: Adv. Mater., 28, 4012-4018

An ambipolar poly(diketopyrrolopyrrole-terthiophene)-based field-effect transistor (FET)sensitively detects xylene isomers at low ppm levels with multiple sensing features. Combined with pattern-recognition algorithms, a sole ambipolar FET sensor, rather than arrays of sensors, can discriminate highly similar xylene structural isomers from one another.

Exhaled Breath Analysis for Monitoring Response to Treatment in Advanced Lung Cancer

Published: March 2016

Authors: Nardi-Agmon, I.; Abud-Hawa, M.; Liran, O.; Gai-Mor, N.; Ilouze, M.; Onn, A.; Bar, J.; Shlomi, D.; Haick, H.; Peled, N.

Years: 2016

Published in: J. Thorac. Oncol., 11 ( 6), 827-837

INTRODUCTION:
The Response Evaluation Criteria in Solid Tumors (RECIST) serve as the accepted standard to monitor treatment efficacy in lung cancer. However, the time intervals between consecutive computerized tomography scans might be too long to allow early identification of treatment failure. This study examines the use of breath sampling to monitor responses to anticancer treatments in patients with advanced lung cancer.

METHODS:
A total of 143 breath samples were collected from 39 patients with advanced lung cancer. The exhaled breath signature, determined by gas chromatography/mass spectrometry and a nanomaterial-based array of sensors, was correlated with the response to therapy assessed by RECIST: complete response, partial response, stable disease, or progressive disease.

RESULTS:
Gas chromatography/mass spectrometry analysis identified three volatile organic compounds as significantly indicating disease control (PR/stable disease), with one of them also significantly discriminating PR/stable disease from progressive disease. The nanoarray had the ability to monitor changes in tumor response across therapy, also indicating any lack of further response to therapy. When one-sensor analysis was used, 59% of the follow-up samples were identified correctly. There was 85% success in monitoring disease control (stable disease/partial response).

CONCLUSION:
Breath analysis, using mainly the nanoarray, may serve as a surrogate marker for the response to systemic therapy in lung cancer. As a monitoring tool, it can provide the oncologist with a quick bedside method of identifying a lack of response to an anticancer treatment. This may allow quicker recognition than does the current RECIST analysis. Early recognition of treatment failure could improve patient care.

Breath Testing as Potential Colorectal Cancer Screening Tool

Published: January 2016

Authors: Amal, H.; Leja, M.; Skapars, R.; Sivins, A.; Ancans, G.; Kikuste, I.; Vanags, A.; Tolmanis, I.; Kirsners, A.; Kupcinskas, L.; Haick, H.

Years: 2016

Published in: Int. J. Cancer, 138 (1), 229-236

Although colorectal cancer (CRC) screening is included in organized programs of many countries worldwide, there is still a place for better screening tools. In this study, 418 breath samples were collected from 65 patients with CRC, 22 with advanced or nonadvanced adenomas, and 122 control cases. All patients, including the controls, had undergone colonoscopy. The samples were analysed with two different techniques. The first technique relied on gas chromatography coupled with mass spectrometry (GC-MS) for identification and quantification of volatile organic compounds (VOCs). The T-test was used to identify significant VOCs (p values < 0.017). The second technique relied on sensor analysis with a pattern recognition method for building a breath pattern to identify different groups. Blind analysis or leave-one-out cross validation was conducted for validation. The GC-MS analysis revealed four significant VOCs that identified the tested groups; these were acetone and ethyl acetate (higher in CRC), ethanol and 4-methyl octane (lower in CRC). The sensor-analysis distinguished CRC from the control group with 85% sensitivity, 94% specificity and 91% accuracy. The performance of the sensors in identifying the advanced adenoma group from the non-advanced adenomas was 88% sensitivity, 100% specificity, and 94% accuracy. The performance of the sensors in identifying the advanced adenoma group was distinguished from the control group was 100% sensitivity, 88% specificity, and 94% accuracy. For summary, volatile marker testing by using sensor analysis is a promising noninvasive approach for CRC screening.

Nanoscale Sensor Technologies for Disease Detection via Volatolomics

Published: December 2015

Authors: Vishinkin, R.; Haick, H.

Years: 2015

Published in: Small, 11 (46), 6142–6164

The detection of many diseases is missed because of delayed diagnoses or the low efficacy of some treatments. This emphasizes the urgent need for inexpensive and minimally invasive technologies that would allow efficient early detection, stratifying the population for personalized therapy, and improving the efficacy of rapid bed-side assessment of treatment. An emerging approach that has a high potential to fulfill these needs is based on so-called “volatolomics”, namely, chemical processes involving profiles of highly volatile organic compounds (VOCs) emitted from body fluids, including breath, skin, urine and blood. This article presents a didactic review of some of the main advances related to the use of nanomaterial-based solid-state and flexible sensors, and related artificially intelligent sensing arrays for the detection and monitoring of disease with volatolomics. The article attempts to review the technological gaps and confounding factors related to VOC testing. Different ways to choose nanomaterial-based sensors are discussed, while considering the profiles of targeted volatile markers and possible limitations of applying the sensing approach. Perspectives for taking volatolomics to a new level in the field of diagnostics are highlighted.

Motivation to Learn in Massive Open Online Courses: Examining Aspects of Language and Social Engagement

Published: November 2015

Authors: Barak, M.; Watted, A.; Haick, H.

Years: 2015

Published in: Computers & Education, 94, 49-60

 Learning is mediated by language of instruction and social engagement. Both factors may play a significant role in understanding motivation to learn in massive open online courses (MOOCs). Therefore, the goal of this study was threefold: a. to compare motivation patterns of MOOC participants who study the same course but in a different language of instruction; b. to examine relationships between motivation gain and diverse modes of engagement; and c. to characterize MOOC completers according to their learning motivation. An exploratory case-study was conducted in the settings of a MOOC in Nanotechnology and Nanosensors, delivered in two languages: English and Arabic. The research sample included 325 participants from the English (N = 289) and Arabic (N = 36) MOOCs. The study applied the mixed methods approach, collecting data via pre- and post-questionnaires, forum posts, and email messages. Findings indicated that regardless the language of instruction, MOOC participants were driven to learn by similar goals, emphasizing intrinsic motivation and self-determination. Findings indicated a positive relationship between motivation gain, the number of messages posted to the online forums, and the number of members in the online study groups. Five types of MOOC completers were identified: problem-solvers, networkers, benefactors, innovation-seekers, and complementary-learners.

In Situ and Real-Time Inspection of Nanoparticle Average Size in Flexible Printed Sensors

Published: November 2015

Authors: Segev-Bar, M.; Ukrainsky, B.; Konvalina, G.; Haick, H.

Years: 2015

Published in: J. Phys. Chem. C., 119 (49), 27521−27528

Nanoparticles play an integral part for the production of contacts and active sensing layers in the fast-developing printed electronic technology on flexible devices. Unfortunately, all currently available techniques for nanoparticle characterization are limited to ex situ and/or off-line processing. Here, we describe a new approach composed of two complementary parts for in situ and real-time estimation of the nanoparticles’ effective diameter on flexible substrates. The first part of the approach is based on measurements of electrical resistance of the device in response to strain, and correlation of the response with the nanoparticles’ diameter. The second part takes place only when measuring the electrical resistance is unfeasible. It is based on UV–vis absorption of the device and correlation of the absorption peak with the nanoparticle diameter based on previous calibration data from strain sensitivity. The new approach shows excellent estimations of the nanoparticle diameter (2.5–20 nm) on the substrate with the advantages of being online, in situ, and inexpensive. In addition, the estimated nanoparticle diameter is in excellent agreement with atomic force microscopy (AFM) measurements. These capabilities are expected to improve the process of “quality control” of the nanoscale-enabled flexible devices, which, until now, has been considered to be one of the most annoying issues that inhibits the commercialization of nanotechnology-based flexible products.

Differentiation Between Genetic Mutations of Breast Cancer by Breath Volatolomics

Published: November 2015

Authors: Barash, O.; Zhang, W.; Halpern, J.M.; Hua, Q.L.; Pan, Y.Y.; Kayal, H.; Khoury, K.; Liu, H.; Davies, M.; Haick, H.

Years: 2015

Published in: Oncotarget, 6, 42, 44864-44876

Mapping molecular sub-types in breast cancer (BC) tumours is a rapidly evolving area due to growing interest in, for example, targeted therapy and screening high-risk populations for early diagnosis. We report a new concept for profiling BC molecular sub-types based on volatile organic compounds (VOCs). For this purpose, breath samples were collected from 276 female volunteers, including healthy, benign conditions, ductal carcinoma in situ (DCIS) and malignant lesions. Breath samples were analysed by gas chromatography mass spectrometry (GC-MS) and artificially intelligent nanoarray technology. Applying the non-parametric Wilcoxon/Kruskal- Wallis test, GC-MS analysis found 23 compounds that were significantly different (p < 0.05) in breath samples of BC patients with different molecular sub-types. Discriminant function analysis (DFA) of the nanoarray identified unique volatolomic signatures between cancer and non-cancer cases (83% accuracy in blind testing), and for the different molecular sub-types with accuracies ranging from 82 to 87%, sensitivities of 81 to 88% and specificities of 76 to 96% in leave-one-out cross-validation. These results demonstrate the presence of detectable breath VOC patterns for accurately profiling molecular sub-types in BC, either through specific compound identification by GC-MS or by volatolomic signatures obtained through statistical analysis of the artificially intelligent nanoarray responses.

Self-Healing, Fully Functional, and Multiparametric Flexible Sensing Platform

Published: November 2015

Authors: Huynh, T. P.; Haick, H.

Years: 2015

Published in: Adv. Mater., 28, 138–143

A non-biological and flexible self-healing platform has tailored sensitivity toward one or a combination of pressure, strain, gas analytes, and temperature. For demonstration, a complete self-healing device is described in the form of a bendable and stretchable chemiresistor, where every part is self-healing.

Dynamic Nanoparticle-Based Flexible Sensors: Diagnosis of Ovarian Carcinoma from Exhaled Breath

Published: October 2015

Authors: Kahn, N.; Lavie, O.; Paz, M.; Segev, Y.; Haick, H.

Years: 2015

Published in: Nano Lett., 15 (10), 7023–7028

Flexible sensors based on molecularly modified gold nanoparticles (GNPs) were integrated into a dynamic cross-reactive diagnostic sensing array. Each bending state of the GNP-based flexible sensor gives unique nanoparticle spatial organization, altering the interaction between GNP ligands and volatile organic compounds (VOCs), which increases the amount of data obtainable from each sensor. Individual dynamic flexible sensor could selectively detect parts per billion (ppb) level VOCs that are linked with ovarian cancers in exhaled breath and discriminate them from environmental VOCs that exist in exhaled breath samples, but do not relate to ovarian cancer per se. Strain-related response successfully discriminated between exhaled breath collected from control subjects and those with ovarian cancer, with data from a single sensor being sufficient to obtain 82% accuracy, irrespective of important confounding factors, such as tobacco consumption and comorbidities. The approach raises the hope of achieving an extremely simple, inexpensive, portable, and noninvasive diagnostic procedure for cancer and other diseases.

Detection of Cancer through Exhaled Breath: A Systematic Review

Published: September 2015

Authors: Krilaviciute, A.; Heiss, J.; Leja, M.; Kupcinskas, J.; Haick, H.; Brenner, H.

Years: 2015

Published in: Oncotarget, 17, 6 (36) 38643-38657

BACKGROUND:

Timely diagnosis of cancer represents a challenging task; in particular, there is a need for reliable non-invasive screening tools that could achieve high levels of adherence at virtually no risk in population-based screening. In this review, we summarize the current evidence of exhaled breath analysis for cancer detection using standard analysis techniques and electronic nose.

METHODS:
Relevant studies were identified searching Pubmed and Web of Science databases until April 30, 2015. Information on breath test performance, such as sensitivity and specificity, was extracted together with volatile compounds that were used to discriminate cancer patients from controls. Performance of different breath analysis techniques is provided for various cancers together with information on methodological issues, such as breath sampling protocol and validation of the results.

RESULTS:
Overall, 73 studies were included, where two-thirds of the studies were conducted on lung cancer. Good discrimination usually required a combination of multiple biomarkers, and area under the receiver operating characteristic curve or accuracy reached levels of 0.9 or higher in multiple studies. In 25% of the reported studies, classification models were built and validated on the same datasets. Huge variability was seen in different aspects among the studies.

CONCLUSIONS:
Analyses of exhaled breath yielded promising results, although standardization of breath collection, sample storage and data handling remain critical issues. In order to foster breath analysis implementation into practice, larger studies should be implemented in true screening settings, paying particular attention to standardization in breath collection, consideration of covariates, and validation in independent population samples.

Hybrid Volatolomics and Disease Detection

Published: September 2015

Authors: Broza, Y. Y.; Mochalski, P.; Ruzsanyi, V.; Amann, A.; Haick, H.

Years: 2015

Published in: Angew. Chem. Int Ed Engl., 54 (38),11036-11048

This Review presents a concise, but not exhaustive, didactic overview of some of the main concepts and approaches related to “volatolomics”-an emerging frontier for fast, risk-free, and potentially inexpensive diagnostics. It attempts to review the source and characteristics of volatolomics through the so-called volatile organic compounds (VOCs) emanating from cells and their microenvironment. It also reviews the existence of VOCs in several bodily fluids, including the cellular environment, blood, breath, skin, feces, urine, and saliva. Finally, the usefulness of volatolomics for diagnosis from a single bodily fluid, as well as ways to improve these diagnostic aspects by “hybrid” approaches that combine VOC profiles collected from two or more bodily fluids, will be discussed. The perspectives of this approach in developing the field of diagnostics to a new level are highlighted.

Hybride Volatolomik und der Nachweis von Krankheiten

Published: September 2015

Authors: Broza, Y. Y.; Mochalski, P.; Ruzsanyi, V.; Amann, A.; Haick, H.

Years: 2015

Published in: Angew. Chem., 127, (38): 11188–11201

Hier stellen wir einige der Hauptkonzepte und Ansätze der Volatolomik, einem sich rasch entwickelnden Gebiet der schnellen, risikofreien und wahrscheinlich preisgünstigen Diagnostik, vor. Wir versuchen, einen Überblick über die Herkunft und die Eigenschaften der Volatolomik anhand von flüchtigen organischen Verbindungen (“volatile organic compounds”, VOCs), die von Zellen und ihrer Mikroumgebung freigesetzt werden, zu geben. Wir beschreiben außerdem das Vorkommen von VOCs in verschiedenen Körperflüssigkeiten, darunter die zelluläre Umgebung, Blut, Atemluft, Haut, Faeces, Urin und Speichel. Schließlich diskutieren wir den Nutzen der Volatolomik für eine Diagnosestellung auf Basis einer einzelnen Körperflüssigkeit ebenso wie die Verbesserung der Diagnosesicherheit durch den “Hybrid”-Ansatz, bei dem die VOC-Profile von zwei oder mehr Körperflüssigkeiten erstellt und kombiniert werden. Die Perspektiven dieser Verfahrensweise zur Weiterentwicklung der Diagnostik werden aufgezeigt.

Application of Organophosphonic Acids by One-Step Supercritical CO2 on 1D and 2D Semiconductors: Toward Enhanced Electrical and Sensing Performances

Published: July 2015

Authors: Bhartia, B.; Bachar, N.; Jayaraman, S.; Khatib, S.; Song, J.; Guo, S.; Troadec, C.; Puniredd, S. R.; Haick, H.

Years: 2015

Published in: Acs Appl. Mater. Interf., 7 (27), 14885–14895

Formation of dense monolayers with proven atmospheric stability using simple fabrication conditions remains a major challenge for potential applications such as (bio)sensors, solar cells, surfaces for growth of biological cells, and molecular, organic, and plastic electronics. Here, we demonstrate a single-step modification of organophosphonic acids (OPA) on 1D and 2D structures using supercritical carbon dioxide (SCCO2) as a processing medium, with high stability and significantly shorter processing times than those obtained by the conventional physisorption-chemisorption method (2.5 h vs 48-60 h).The advantages of this approach in terms of stability and atmospheric resistivity are demonstrated on various 2D materials, such as indium-tin-oxide (ITO) and 2D Si surfaces. The advantage of the reported approach on electronic and sensing devices is demonstrated by Si nanowire field effect transistors (SiNW FETs), which have shown a few orders of magnitude higher electrical and sensing performances, compared with devices obtained by conventional approaches. The compatibility of the reported approach with various materials and its simple implementation with a single reactor makes it easily scalable for various applications.

Controlling the Sensing Properties of Silicon Nanowires via the Bonds Nearest to the Silicon Nanowire Surface

Published: May 2015

Authors: Halpern, J.M.; Wang, B.; Haick, H.

Years: 2015

Published in: Acs Appl. Mater. Interf., 7 (21), 11315-11321

Controlling the sensing properties of a silicon nanowire field effect transistor is dependent on the surface chemistry of the silicon nanowire. A standard silicon nanowire has a passive oxide layer (native oxide), which has trap states that cause sensing inaccuracies and desensitize the surface to nonpolar molecules. In this paper, we successfully modified the silicon nanowire surface with different nonoxide C3 alkyl groups, specifically, propyl (Si-CH2-CH2-CH3), propenyl (Si-CH═CH-CH3), and propynyl (Si-C≡C-CH3) modifications. The effect of the near surface bond on the sensor sensitivity and stability was explored by comparing three C3 surface modifications. A reduction of trap-states led to greater sensor stability and accuracy. The propenyl-modified sensor was consistently the most stable and sensitive sensor, among the applied sensors. The propenyl- and propynyl-modified sensors consistently performed with the best accuracy in identifying specific analytes with similar polarity or similar molecular weights. A combination of features from different sensing surfaces led to the best rubric for specific analytes identification. These results indicate that nonoxide sensor surfaces are useful in identifying specific analytes and that a combination of sensors with different surfaces in a cross-reactive array can lead to specific analytes detection.

Printing Nanostructures with a Propelled Anti-​Pinning Ink Droplet

Published: April 2015

Authors: Konvalina, G.; Leshansky, M.A.; Haick, H.

Years: 2015

Published in: Adv. Func. Mater., 25(16), 2411-2419.

Striving for cheap and robust manufg. processes has prompted efforts to adapt and extend methods for printed electronics and biotechnol. A new “direct-​write” printing method for patterning nanometeric species in addressable locations has been developed, by means of evaporative deposition from a propelled anti-​pinning ink droplet (PAPID) in a manner analogous to a snail-​trail. Three velocity-​controlled deposition regimes have been identified; each spontaneously produces distinct and well-​defined self-​assembled deposition patterns. Unlike other technologies that rely on overlapping droplets, PAPIDs produce continuous patterns that can be formed on rigid or flexible substrates, even within 3D concave closed shapes, and have the ability to control the thickness gradient along the pattern. This versatile low cost printing method can produce a wide range of unusual electronic systems not attainable by other methods.

Detection of Precancerous Gastric Lesions and Gastric Cancer through Exhaled Breath

Published: April 2015

Authors: Amal, H.; Leja, M.; Funka, K.; Skapars, R.; Sivins, A.; Ancans, G.; Liepniece-Karele, I.; Kikuste, I.; Lasina, I.; Haick, H.

Years: 2015

Published in: Gut., 65, 400–407 (2016)

Objectives Timely detection of gastric cancer (GC) and the related precancerous lesions could provide a tool for decreasing both cancer mortality and incidence.

Design 968 breath samples were collected from 484 patients (including 99 with GC) for two different analyses. The first sample was analysed by gas chromatography linked to mass spectrometry (GCMS) while applying t test with multiple corrections (p value<0.017); the second by cross-reactive nanoarrays combined with pattern recognition. For the latter, 70% of the samples were randomly selected and used in the training set while the remaining 30% constituted the validation set. The operative link on gastric intestinal metaplasia (OLGIM) assessment staging system was used to stratify the presence/absence and risk level of precancerous lesions. Patients with OLGIM stages III–IV were considered to be at high risk.

Results According to the GCMS results, patients with cancer as well as those at high risk had distinctive breath-print compositions. Eight significant volatile organic compounds (p value<0.017) were detected in exhaled breath in the different comparisons. The nanoarray analysis made it possible to discriminate between the patients with GC and the control group (OLGIM 0–IV) with 73% sensitivity, 98% specificity and 92% accuracy. The classification sensitivity, specificity, and accuracy between the subgroups was as follows: GC versus OLGIM 0–II—97%, 84% and 87%; GC versus OLGIM III–IV—93%, 80% and 90%; but OLGIM I–II versus OLGIM III–IV and dysplasia combined—83%, 60% and 61%, respectively.

Conclusions Nanoarray analysis could provide the missing non-invasive screening tool for GC and related precancerous lesions as well as for surveillance of the latter.

Assessment of Ovarian Cancer Conditions from Exhaled Breath

Published: March 2015

Authors: Amal, H.; Shi, D. Y.; Ionescu, R.; Zhang, W.; Hua, Q.L.; Pan, Y.Y.; Tao, L.; Liu, H.; Haick, H.

Years: 2015

Published in: Int. J. Cancer, 136, E614–E622

We present a pilot study that aims to examine the possibility to easily and noninvasively detect and discriminate females with ovarian cancer (OC) from females that have no tumor(s) and from females that have benign genital tract neoplasia, using exhaled breath samples. The study is based on clinical samples and data from 182 females, as follows: 48 females with OC, 48 tumor-free controls and 86 females with benign gynecological neoplasia. Analysis of the breath samples with gas chromatography linked with mass spectrometry shows that decanal, nonanal, styrene, 2-butanone and hexadecane could serve as potential volatile markers for OC. Analysis of the same samples with tailor-made nanoarrays shows good discrimination between females with OC and females that have either no tumor or benign genital tract neoplasia (71% for accuracy, sensitivity and specificity). Conversely, the nanoarray output shows excellent discrimination between the OC patients and the tumor-free controls (79% sensitivity, 100% specificity and 89% accuracy). These results suggest that the nanoarray approach might be useful to avoid unnecessary complicated or expensive tests for tumor-free females in case of a negative result. In the case of positive result, the test will indicate with high probability the presence of OC.

High-Resolution Unpixelated Smart Patches with Antiparallel Thickness Gradients of Nanoparticles

Published: March 2015

Authors: Segev-Bar, M.; Konvalina, G.; Haick, H.

Years: 2015

Published in: Adv. Mater., 27 (10), 1779-1784

A new concept for high-resolution sensing of touch/load and location in which the number of pixels can be significantly diminished is presented. The technology is based on a flexible substrate with two parallel gold-nanoparticle strips with antiparallel sensitivity gradients for an unpixelated skin strip. The approach exhibits high location and load resolutions.

Role of Silicon Nanowire Diameter for Alkyl (Chain Lengths C₁-C₁₈) Passivation Efficiency through Si-C Bonds

Published: March 2015

Authors: Bashouti, M. Y.; Garzuzi, C.A.; de la Mata, M.; Arbiol, J.; Ristein, J.; Haick, H.; Christiansen, S.

Years: 2015

Published in: Langmuir, 31 (8), 2430-2437

The effect of silicon nanowire (Si NW) diameter on the functionalization efficiency as given by covalent Si-C bond formation is studied for two distinct examples of 25 ± 5 and 50 ± 5 nm diameters (Si NW25 and Si NW50, respectively). A two-step chlorination/alkylation process is used to connect alkyl chains of various lengths (C1-C18) to thinner and thicker Si NWs. The shorter the alkyl chain lengths, the larger the surface coverage of the two studied Si NWs. Increasing the alkyl chain length (C2-C9) changes the coverage on the NWs: while for Si NW25 90 ± 10% of all surface sites are covered with Si-C bonds, only 50 ± 10% of all surface sites are covered with Si-C bonds for the Si NW50 wires. Increasing the chain length further to C14-C18 decreases the alkyl coverage to 36 ± 6% in thin Si NW25 and to 20 ± 5% in thick Si NW50. These findings can be interpreted as being a result of increased steric hindrance of Si-C bond formation for longer chain lengths and higher surface energy for the thinner Si NWs. As a direct consequence of these findings, Si NW surfaces have different stabilities against oxidation: they are more stable at higher Si-C bond coverage, and the surface stability was found to be dependent on the Si-C binding energy itself. The Si-C binding energy differs according to (C1-9)-Si NW > (C14-18)-Si NW, i.e., the shorter the alkyl chain, the greater the Si-C binding energy. However, the oxidation resistance of the (C2-18)-Si NW25 is lower than for equivalent Si NW50 surfaces as explained and experimentally substantiated based on electronic (XPS and KP) and structure (TEM and HAADF) measurements.

Distinguishing Idiopathic Parkinson’s Disease from Other Parkinsonian Syndromes by Breath Test

Published: February 2015

Authors: Nakhleh, K. M.; Winer, R.; Jeries, R.; Finberg, J.P.M.; Haick, H.

Years: 2015

Published in: Parkinsonism Relat Disord., 21 (2), 150-153

INTRODUCTION:
Diagnosis of different parkinsonian syndromes is linked with high misdiagnosis rates and various confounding factors. This is particularly problematic in its early stages. With this in mind, the current pilot study aimed to distinguish between Idiopathic Parkinson’s Disease (iPD), other Parkinsonian syndromes (non-iPD) and healthy subjects, by a breath test that analyzes the exhaled volatile organic compounds using a highly sensitive nanoarray.
METHODS:
Breath samples of 44 iPD, 16 non-iPD patients and 37 healthy controls were collected. The samples were passed over a nanoarray and the resulting electrical signals were analyzed with discriminant factor analysis as well as by a K-fold cross-validation method, to test the accuracy of the model.
RESULTS:
Comparison of non-iPD with iPD states yielded 88% sensitivity, 88% accuracy, and 88% Receiver Operating Characteristic area under the curve in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and accuracy and 92% negative predictive value. Comparison between atypical parkinsonism states and healthy subjects scored 94% sensitivity and 85% accuracy in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and 78% accuracy. The obtained results were not affected by l-Dopa or MAO-B inhibitor treatment.
CONCLUSIONS:
Exhaled breath analysis with nanoarray is a promising approach for a non-invasive, inexpensive, and portable technique for differentiation between different Parkinsonian states. A larger cohort is required in order to establish the clinical usefulness of the method.

Detecting Lung Infections in Breathprints: Empty Promise or Next Generation Diagnosis of Infections

Published: January 2015

Authors: Haick, H.; Cohen-Kaminsky, S.

Years: 2015

Published in: Eur Respir J., 45 (1), 21-24

Comment on
Breathprints of model murine bacterial lung infections are linked with immune response. [Eur Respir J. 2015]

A discussion of evidence on the link between breathprints of bacterial lung infections and the immune response

Assessment of Ovarian Cancer Conditions from Exhaled Breath

Published: September 2014

Authors: Amal, H.; Shi, D. Y.; Ionescu, R.; Zhang, W.; Hua, Q.L.; Pan, Y.Y.; Tao, L.; Liu, H.; Haick, H.

Years: 2014

Published in: Int. J. Cancer, 136, E614–E622

ABSTRACT: Most patients with ovarian cancer (OC) are diagnosed with advanced disease stages (III to IV) and have a 5-year survival rate less than 30%. Detecting OC in its early stages before it has metastasized could increase the 5-year survival rate to 85% to 90%. Previous studies have investigated a novel approach for the detection of OC based on measuring volatile organic compounds (VOCs) in exhaled breath; these disease-specific compounds evaporate from cancer cells and enter the surrounding environment. Using this principle, trained dogs showed an ability to distinguish OC tissues or blood samples from equivalent controls with almost 100% sensitivity and specificity. Because canine OC detection is not practical for widespread clinical use, scientists developed suitably sensitive analytical instrumentation for rapid detection of OC with similar accuracy as found with dogs.
This pilot study examined the possibility that exhaled breath samples can noninvasively detect and discriminate women with OC from women that have no tumor(s) and from women that have benign genital tract neoplasia. The study population was composed of 3 groups: women with OC (n = 48), tumor-free control subjects (n = 48), and women with benign genetic tract neoplasia (n = 86). Gas chromatography linked with mass spectrometry was used to determine the chemical composition of the VOCs in the breath samples. Elevated concentrations of 5 compounds (decanal, nonanal, styrene, 2-butanone, and hexadecane) were found in the VOC samples from patients with cancer compared with the cancer-free volunteers.
Analysis of the same samples with tailor-made nanoarrays showed good discrimination between women with OC and women who had either no tumor or benign genital tract neoplasia (71% for accuracy, sensitivity, and specificity). Conversely, nanoarray analysis was able to distinguish between the OC patients and the tumor-free control subjects (79% sensitivity, 100% specificity, and 89% accuracy).
These preliminary findings show that a negative result with nanorray analysis could identify tumor-free women and avoid unnecessary complicated or expensive tests for OC in these patients. In patients with a positive result, the test will indicate the presence of OC with high probability. Further studies are needed with larger and more diverse populations to confirm and improve these promising results.

Monolayer-Capped Gold Nanoparticles for Disease Detection from Breath

Published: September 2014

Authors: Nakhleh, K. M.; Broza, Y. Y.; Haick, H.

Years: 2014

Published in: Nanomedicine (Lond)., 9(13), 1991–2002

The recognition of volatile organic compounds in breath samples is a promising approach for noninvasive safe diagnosis of disease. Spectrometry and spectroscopy methods used for breath analysis suffer from suboptimal accuracy, are expensive and are unsuitable for diagnostics. This article presents a concise review on arrays of monolayer-capped gold nanoparticle (GNP) sensors in conjugation with pattern recognition methods for cost-effective, fast and high-throughput point-of-care diagnostic results from exhaled breath samples. The article starts with a general introduction to the rationale and advantages of breath analysis as well as with a presentation of the utility of monolayer-capped GNP sensors in this field. The article continues with a presentation of the main fabrication and operation principles of these GNP sensors and concludes with selected examples regarding their utility in different fields of medicine, particularly in neurology, infectiology, respiratory medicine and oncology.

Unique Volatolomic Signatures of TP53 and KRAS in Lung Cells

Published: July 2014

Authors: Davies, M.; Barash, O.; Jeries, R.; Peled, N.; Ilouze, M.; Hyde, R.; Marcus, M.W.; Field, J.K.; Haick, H.

Years: 2014

Published in: Br. J. Cancer, 111, 1213–1221

background:
Volatile organic compounds (VOCs) are potential biomarkers for cancer detection in breath, but it is unclear if they reflect specific mutations. To test this, we have compared human bronchial epithelial cell (HBEC) cell lines carrying the KRASV12 mutation, knockdown of TP53 or both with parental HBEC cells.
methods:
VOC from headspace above cultured cells were collected by passive sampling and analysed by thermal desorption gas chromatography mass spectrometry (TD-GC–MS) or sensor array with discriminant factor analysis (DFA).
results:
In TD-GC–MS analysis, individual compounds had limited ability to discriminate between cell lines, but by applying DFA analysis combinations of 20 VOCs successfully discriminated between all cell types (accuracies 80–100%, with leave-one-out cross validation). Sensor array detection DFA demonstrated the ability to discriminate samples based on their cell type for all comparisons with accuracies varying between 77% and 93%.
conclusions:
Our results demonstrate that minimal genetic changes in bronchial airway cells lead to detectable differences in levels of specific VOCs identified by TD-GC–MS or of patterns of VOCs identified by sensor array output. From the clinical aspect, these results suggest the possibility of breath analysis for detection of minimal genetic changes for earlier diagnosis or for genetic typing of lung cancers.

Analysis of Exhaled Breath for Diagnosing Head and Neck Squamous Cell Carcinoma:A Feasibility Study

Published: July 2014

Authors: Tisch, U.; Jeries, R.; Amal, H.; Hakim, M.; Gruber, M.; Ronen, O.; Marshak, T.; Zimmerman, D.; Israel, O.; Amiga, E.; Doweck, I.; Haick, H.

Years: 2014

Published in: Br. J. Cancer, 111, 790–798

BACKGROUND:
Squamous cell carcinoma of the head and neck (HNSCC) are wide-spread cancers that often lead to disfigurement and loss of important functions such as speech and ingestion. To date, HNSCC has no adequate method for early detection and screening.

METHODS:
Exhaled breath samples were collected from 87 volunteers; 62 well-defined breath samples from 22 HNSCC patients (larynx and pharynx), 21 patients with benign tumours (larynx and pharynx) and 19 healthy controls were analysed in a dual approach: (i) chemical analysis using gas chromatography/mass spectrometry (GC-MS) and (ii) breath-print analysis using an array of nanomaterial-based sensors, combined with a statistical algorithm.

RESULTS:
Gas chromatography/mass spectrometry identified ethanol, 2-propenenitrile and undecane as potential markers for HNSCC and/or benign tumours of the head and neck. The sensor-array-based breath-prints could clearly distinguish HNSCC both from benign tumours and from healthy states. Within the HNSCC group, patients could be classified according to tumour site and stage.

CONCLUSIONS:
We have demonstrated the feasibility of a breath test for a specific, clinically interesting application: distinguishing HNSCC from tumour-free or benign tumour states, as well as for staging and locating HNSCC. The sensor array used here could form the basis for the development of an urgently needed non-invasive, cost-effective, fast and reliable point-of-care diagnostic/screening tool for HNSCC.

Sensor Arrays Based on Nanoparticles for Early Detection of Kidney Injury by Breath Samples

Published: June 2014

Authors: Nakhleh, K. M.; Amal, H.; Awad, H.; Gharra, A.; Abu-Saleh, N.; Jeries, R.; Haick, H.; Abassi, Z.

Years: 2014

Published in: Nanomedicine, 1767-1776

The outcomes of acute kidney injury (AKI) could be severe and even lethal, if not diagnosed in its early stages and treated appropriately. Blood and urine biomarkers, currently in use as indicators for kidney function, are either inaccurate in various cases or not timely. We report on dramatic changes in exhaled breath composition, associated with kidney dysfunction after ischemic insult in rat models. Gas chromatography linked mass spectrometry examination of breath samples indicated significant elevations in the concentration of three exhaled volatile organic compounds, two to six hours after AKI was surgically induced. Relying on these findings, we introduce an array of sensors, based on organic-layer capped gold nanoparticles, sensitive to odor changes. The ability of the array to detect AKI via breath testing was examined and scored a sensitivity of 96%, only one hour after disease induction.

FROM THE CLINICAL EDITOR:
In this study, organic-layer capped gold nanoparticle-based biosensors are used to analyse breath samples in an acute kidney injury model, capitalizing on the observation that specific volatile organic compounds are present in breath samples in that condition. The authors report excellent sensitivity in as little as one hour after acute kidney injury. This method, if commercialized, may replace the current blood and urine sample analysis-based tests with a more convenient, rapid and accurate nanotechnology-based method.

Detecting Active Pulmonary Tuberculosis with a Breath Test Using Nanomaterial Based Sensors

Published: May 2014

Authors: Nakhleh, K. M.; Jeries, R.; Gharra, A.; Binder, A.; Broza, Y. Y.; Pascoe, M.; Dheda, K.; Haick, H.

Years: 2014

Published in: Eur Respir J., 43, 1519–1522

Combined Volatolomics for Monitoring of Human Body Chemistry

Published: April 2014

Authors: Broza, Y. Y.; Zuri, L.; Haick, H.

Years: 2014

Published in: Sci. Rep., 4, 4611

Analysis of volatile organic compounds (VOCs) is a promising approach for non-invasive, fast and potentially inexpensive diagnostics. Here, we present a new methodology for profiling the body chemistry by using the volatile fraction of molecules in various body fluids. Using mass spectrometry and cross-reactive nanomaterial-based sensors array, we demonstrate that simultaneous VOC detection from breath and skin would provide complementary, non-correlated information of the body’s volatile metabolites profile. Eventually with further wide population validation studies, such a methodology could provide more accurate monitoring of pathological changes compared to the information provided by a single body fluid. The qualitative and quantitative methods presented here offers a variety of options for novel mapping of the metabolic properties of complex organisms, including humans.

Artificial Sensing Intelligence with Silicon Nanowires for Ultraselective Detection in the Gas Phase

Published: January 2014

Authors: Wang, B.; Cancilla, J.C.; Torrecilla, J.S.; Haick, H.

Years: 2014

Published in: Nano Lett., 14, 933−938

The use of molecularly modified Si nanowire field effect transistors (SiNW FETs) for selective detection in the liquid phase has been successfully demonstrated. In contrast, selective detection of chemical species in the gas phase has been rather limited. In this paper, we show that the application of artificial intelligence on deliberately controlled SiNW FET device parameters can provide high selectivity toward specific volatile organic compounds (VOCs). The obtained selectivity allows identifying VOCs in both single-component and multicomponent environments as well as estimating the constituent VOC concentrations. The effect of the structural properties (functional group and/or chain length) of the molecular modifications on the accuracy of VOC detection is presented and discussed. The reported results have the potential to serve as a launching pad for the use of SiNW FET sensors in real-world counteracting conditions and/or applications.

Assessment, Origin, and Implementation of Breath Volatile Cancer Markers

Published: December 2013

Authors: Haick, H.; Broza, Y. Y.; Mochalski, P.; Ruzsanyi, V.; Amann, A.

Years: 2013

Published in: Chem. Soc. Rev., 43, 1423-1449

A new non-invasive and potentially inexpensive frontier in the diagnosis of cancer relies on the detection of volatile organic compounds (VOCs) in exhaled breath samples. Breath can be sampled and analyzed in real-time, leading to fascinating and cost-effective clinical diagnostic procedures. Nevertheless, breath analysis is a very young field of research and faces challenges, mainly because the biochemical mechanisms behind the cancer-related VOCs are largely unknown. In this review, we present a list of 115 validated cancer-related VOCs published in the literature during the past decade, and classify them with respect to their “fat-to-blood” and “blood-to-air” partition coefficients. These partition coefficients provide an estimation of the relative concentrations of VOCs in alveolar breath, in blood and in the fat compartments of the human body. Additionally, we try to clarify controversial issues concerning possible experimental malpractice in the field, and propose ways to translate the basic science results as well as the mechanistic understanding to tools (sensors) that could serve as point-of-care diagnostics of cancer. We end this review with a conclusion and a future perspective.

Detection of Volatile Organic Compounds in Brucella abortus- Seropositive Bison

Published: November 2013

Authors: Bayn, A.; Nol, P.; Tisch, U.; Rhyan, J.; Ellis, C.K.; Haick, H.

Years: 2013

Published in: Anal. Chem., 85, 11146−11152

Brucellosis is of great public health and economic importance worldwide. Detection of brucellosis currently relies on serologic testing of an antibody response to Brucella infection, which suffers from cross-sensitivities to other antibody responses. Here we present a new method for identifying Brucella exposure that is based on profiling volatile organic compounds (VOCs) in exhaled breath. Breath samples from Brucella-seropositive bison and controls were chemically analyzed and demonstrated statistically significant differences in the concentration profiles of five VOCs. A point-of-care device incorporating an array of nanomaterial-based sensors could identify VOC patterns indicative of Brucella exposure with excellent discriminative power, using a statistical algorithm. We show that the patterns were not affected by the animals’ environment and that the discriminative power of the approach was stable over time. The Brucella-indicative VOCs and collective patterns that were identified in this pilot study could lead to the development of a novel diagnostic screening test for quickly detecting infected animals chute-side, pen-side, or even remotely in populations of free-ranging ungulates. The promising preliminary results presented encourage subsequent larger scale trials in order to further evaluate the proposed method.

Geographical Variation in the Exhaled Volatile Organic Compounds

Published: November 2013

Authors: Amal, H.; Leja, M.; Broza, Y. Y.; Tisch, U.; Funka, K.; Liepniece-Karele, I.; Skapars, R.; Xu, Z. Q.; Liu, H.; Haick, H.

Years: 2013

Published in: J. Breath Res., 7, 1-9

Breath-gas analysis has demonstrated that concentration profiles of volatile organic compounds (VOCs) could be used for detecting a variety of diseases, among them gastric cancer (GC) and peptic ulcer disease (PUD). Here, we explore how geographical variation affects the disease-specific changes in the chemical composition of breath samples, as compared to control states (less severe gastric conditions). Alveolar exhaled breath samples from 260 patients were collected at two remotely different geographic locations (China and Latvia), following similar breath-collection protocols. Each cohort included 130 patients that were matched in terms of diagnosis (37 GC/32 PUD/61 controls), average age, gender ratio and smoking habits. Helicobacter Pylori infection, which is a major cause for GC and PUD, was found in part of the patients, as well as in part of the controls, at both locations. The breath samples were analyzed by gas chromatography/mass spectrometry, using the same equipment and protocol-of-experiment. We observed similar characteristic differences in the chemical composition of the breath samples between the study groups at the two locations, even though the exact composition of the breath samples differed. Both in China and Latvia, the GC patients and controls could be distinguished by differences in the average levels of 6-methyl-5-hepten-2-one; PUD patients were distinguished from controls by the levels of aromatic compounds and alcohols; GC and PUD patients could not be distinguished at either site. This pilot study indicates the limitations of chemical breath-gas analysis alone for identifying gastric diseases based on the concentration profiles of separate VOCs in international patient cohorts. We assume that these limitations would apply to other diseases as well. The presented data could potentially be useful for developing an alternative, universally applicable diagnostic method that relies on the detection of changes in the collective patterns of the disease-specific classes of exhaled VOCs.

Sensor Arrays Based on Polycyclic Aromatic Hydrocarbons: Chemiresistors versus Quartz-Crystal Microbalance

Published: October 2013

Authors: Bachar, N.; Liberman, L.; Muallem, F.; Feng, X.; Müllen, K.; Haick, H.

Years: 2013

Published in: Acs Appl. Mater. Interf., 5, 11641−11653

Arrays of broadly cross-reactive sensors are key elements of smart, self-training sensing systems. Chemically sensitive resistors and quartz-crystal microbalance (QCM) sensors are attractive for sensing applications that involve detection and classification of volatile organic compounds (VOCs) in the gas phase. Polycyclic aromatic hydrocarbon (PAH) derivatives as sensing materials can provide good sensitivity and robust selectivity towards different polar and nonpolar VOCs, while being quite tolerant to large humidity variations. Here, we present a comparative study of chemiresistor and QCM arrays based on a set of custom-designed PAH derivatives having either purely nonpolar coronas or alternating nonpolar and strongly polar side chain termination. The arrays were exposed to various concentrations of representative polar and nonpolar VOCs under extremely varying humidity conditions (5–80% RH). The sensor arrays’ classification ability of VOC polarity, chemical class and compound separation was explained in terms of the sensing characteristics of the constituent sensors and their interaction with the VOCs. The results presented here contribute to the development of novel versatile and cost-effective real-world VOC sensing platforms.

Discriminative Power of Chemically Sensitive Silicon Nanowire Field Effect Transistors to Volatile Organic Compounds

Published: October 2013

Authors: Ermanok, R; Assad, O.; Zigelboim, K.; Wang, B.; Haick, H.

Years: 2013

Published in: Acs Appl. Mater. Interf., 5, 11172−11183

We report on the sensing of different polar and nonpolar volatile organic compounds (VOCs) in an atmosphere with background humidity (relative humidity: 40%), using molecularly modified silicon nanowire field effect transistors (SiNW FETs). In this endeavor, a systematic comparative analysis is performed with: (i) SiNW FETs that were functionalized with a series of molecules having different electron-withdrawing and electron-donating end groups; and (ii) SiNW FETs that are functionalized with a series of molecules having similar functional groups but different backbone lengths. The analysis of the sensing signals are focused on three main FET parameters: (i) changes in the threshold voltage, (ii) changes in the carrier mobility, and (iii) changes in the on-current, compared to the baseline values under vacuum. Using discriminant factor analysis, the performance of the molecularly modified SiNW FETs is further analyzed as sensors array. The combination of sensors having the best discriminative power between the various VOCs are identified and discussed in terms of their constituent surface modifications.

A Proof of Concept for the Detection and Classification of Pulmonary Arterial Hypertension through Breath Analysis with a Sensor Array

Published: September 2013

Authors: Cohen-Kaminsky, S.; Nakhleh, K. M.; Perros, F.; Montani, D.; Girerd, B.; Garcia, G.; Simonneau, G.; Haick, H.; Humbert, M.

Years: 2013

Published in: Am. J. Resp. Crit. Care Med., 188, 756-759

Flexible Sensors Based on Nanoparticles

Published: September 2013

Authors: Segev-Bar, M.; Haick, H.

Years: 2013

Published in: ACS Nano., 7, 8366-8378

Flexible sensors can be envisioned as promising components for smart sensing applications, including consumer electronics, robotics, prosthetics, health care, safety equipment, environmental monitoring, homeland security and space flight. The current review presents a concise, although admittedly nonexhaustive, didactic review of some of the main concepts and approaches related to the use of nanoparticles (NPs) in flexible sensors. The review attempts to pull together different views and terminologies used in the NP-based sensors, mainly those established via electrical transduction approaches, including, but, not confined to: (i) strain-gauges, (ii) flexible multiparametric sensors, and (iii) sensors that are unaffected by mechanical deformation. For each category, the review presents and discusses the common fabrication approaches and state-of-the-art results. The advantages, weak points, and possible routes for future research, highlighting the challenges for NP-based flexible sensors, are presented and discussed as well.

Sensors for Breath Testing: From Nanomaterials to Comprehensive Disease Detection

Published: August 2013

Authors: Konvalina, G.; Haick, H.

Years: 2013

Published in: Acc. Chem. Res., 47(1), 66–76

The analysis of volatile organic compounds in exhaled breath samples represents a new frontier in medical diagnostics because it is a noninvasive and potentially inexpensive way to detect illnesses. Clinical trials with spectrometry and spectroscopy techniques, the standard volatile-compound detection methods, have shown the potential for diagnosing illnesses including cancer, multiple sclerosis, Parkinson’s disease, tuberculosis, diabetes, and more via breath tests. Unfortunately, this approach requires expensive equipment and high levels of expertise to operate the necessary instruments, and the tests must be done quickly and use preconcentration techniques, all of which impede its adoption.

Sensing matrices based on nanomaterials are likely to become a clinical and laboratory diagnostic tool because they are significantly smaller, easier-to-use, and less expensive than spectrometry or spectroscopy. An ideal nanomaterial-based sensor for breath testing should be sensitive at very low concentrations of volatile organic compounds, even in the presence of environmental or physiological confounding factors. It should also respond rapidly and proportionately to small changes in concentration and provide a consistent output that is specific to a given volatile organic compound. When not in contact with the volatile organic compounds, the sensor should quickly return to its baseline state or be simple and inexpensive enough to be disposable.

Several reviews have focused on the methodological, biochemical, and clinical aspects of breath analysis in attempts to bring breath testing closer to practice for comprehensive disease detection. This Account pays particular attention to the technological gaps and confounding factors that impede nanomaterial-sensor-based breath testing, in the hope of directing future research and development efforts towards the best possible approaches to overcome these obstacles. We discuss breath testing as a complex process involving numerous steps, each of which has several possible technological alternatives with advantages and drawbacks that might affect the performance of the nanomaterial-based sensors in a breath-testing system. With this in mind, we discuss how to choose nanomaterial-based sensors, considering the profile of the targeted breath markers and the possible limitations of the approach, and how to design the surrounding breath-testing setup. We also discuss how to tailor the dynamic range and selectivity of the applied sensors to detect the disease-related volatile organic compounds of interest. Finally, we describe approaches to overcome other obstacles by improving the sensing elements and the supporting techniques such as preconcentration and dehumidification.

Volatile Fingerprints of Cancer Specific Genetic Mutations

Published: August 2013

Authors: Peled, N.; Barash, O.; Tisch, U.; Ionescu, R.; Broza, Y. Y.; Ilouze, M.; Mattei, J.; Bunn, P. A. Jr.; Hirsch, F. R.; Haick, H.

Years: 2013

Published in: Nanomedicine, 9, (6), 758–766

We report on a new concept for profiling genetic mutations of (lung) cancer cells, based on the detection of patterns of volatile organic compounds (VOCs) emitted from cell membranes, using an array of nanomaterial-based sensors. In this in-vitro pilot study we have derived a volatile fingerprint assay for representative genetic mutations in cancer cells that are known to be associated with targeted cancer therapy. Five VOCs were associated with the studied oncogenes, using complementary chemical analysis, and were discussed in terms of possible metabolic pathways. The reported approach could lead to the development of novel methods for guiding treatments, so that patients could benefit from safer, more timely and effective interventions that improve survival and quality of life while avoiding unnecessary invasive procedures. Studying clinical samples (tissue/blood/breath) will be required as next step in order to determine whether this cell-line study can be translated into a clinically useful tool.

Breath Testing: The Future for Digestive Cancer Detection

Published: July 2013

Authors: Leja, M.; Liu, H.; Haick, H.

Years: 2013

Published in: Expert Rev, 7(5), 389–391

A Non-Oxidative Approach Towards Hybrid Silicon Nanowire-Based Solar Cell Heterojunctions

Published: June 2013

Authors: Bashouti, M. Y.; Ristein, J.; Haick, H.; Christiansen, S.

Years: 2013

Published in: Hybrid Mater., 2-14

A general method for the non-oxidative termination of silicon nanowires (Si NWs) is reviewed. Oxide-free Si NW have been successfully alkylated in the lab using a two-step chlorination/alkylation process. The distinctive properties of the resulting Si NW have been taken advantage of by integrating the Si NWs into functional devices such as solar cells. Moreover, molecularly terminated Si NWs exhibit lower defect density emissions than unmodified Si NWs. This, in part, explains the better performance of the molecularly terminated Si NW-based solar cells. Solar cells that use organic-inorganic hybrid Si NWs as absorbers show an increased open-circuit voltage (Voc), an increased short-circuit current (Jsc) and a higher fill factor (FF). The aim of chemical functionalization is to protect Si NWs from extensive oxidation, add functionality and to adjust surface electronic properties such as the work function, surface Fermi level and band bending. The stability of the terminated of Si NWs was found to be dependent on the molecular chain length, molecular coverage, interaction type (π-π or σ-σ), surface energy and Si NW diameter.

Tunable Touch Sensor and Combined Sensing Platform: Toward Nanoparticle-based Electronic Skin

Published: June 2013

Authors: Segev-Bar, M.; Landman, A.; Nir-Shapira, M.; Shuster, G.; Haick, H.

Years: 2013

Published in: Acs Appl. Mater. Interf., 5 (12), 5531-5541

In this paper, we present touch (or pressure) flexible sensors based on monolayer-capped nanoparticles (MCNPs) that are potentially inexpensive, could allow low-voltage operation, and could provide a platform for multifunctional applications. We show that modifying the mechanical and geometrical properties of the flexible substrates, on which the MCNP films are deposited, allows measuring a large span of loads ranging between tens of mg to tens of grams. All flexible sensors exhibited repeatable responses even after a large number of bending cycles. In addition, we show that modified platforms of those touch (or pressure) sensors allow precise detection and monitoring of environmental temperature and humidity. Relying on their superior characteristics, we were able to build an MCNP-based prototype allowing simultaneous detection and monitoring of multiple environmental parameters of touch (or pressure), humidity, and temperature. The excellent temperature (resolution higher than 1 °C and average error of ∼5%) and relative humidity (resolution higher than 1% RH and average error of ∼9%) sensitivities and the possibility to integrate those sensing abilities makes the suggested platform interesting for potentially inexpensive and low-voltage multifunctional electronic-skin applications.

Effect of Chain Length on the Sensing of Volatile Organic Compounds by means of Silicon Nanowires

Published: June 2013

Authors: Wang, B.; Haick, H.

Years: 2013

Published in: Acs Appl. Mater. Interf., 5 (12), 5748−5756

Molecularly modified silicon nanowire field effect transistors (SiNW FETs) are starting to appear as promising devices for sensing various volatile organic compounds (VOCs). Understanding the connection between the molecular layer structure attached to the SiNWs and VOCs is essential for the design of high performance sensors. Here, we explore the chain length influence of molecular layers on the sensing performance to polar and nonpolar VOCs. SiNW FETs were functionalized with molecular layers that have similar end (methyl) group and amide bridge bond, but differ in their alkyl chain lengths. The resulting devices were then exposed to polar and nonpolar VOCs in various concentrations. Our results showed that the sensing response to changing the threshold voltage (ΔVth) and changing the relative hole mobility (Δμh/μh-a) have a proportional relationship to the VOC concentration. On exposure to a specific VOC concentration, ΔVth response increased with the chain length of the molecular modification. In contrast, Δμh/μh-a did not exhibit any obvious reliance on the chain length of the molecular layer. Analysis of the responses with an electrostatic-based model suggests that the sensor response in ΔVth is dependent on the VOC concentration, VOC vapor pressure, VOC–molecular layer binding energy, and VOC adsorption-induced dipole moment changes of molecular layer.

Nanomaterial-Based Sensors for Detection of Disease by Volatile Organic Compounds

Published: May 2013

Authors: Broza, Y. Y.; Haick, H.

Years: 2013

Published in: Nanomedicine, 8 (5), 785–806

The importance of developing new diagnostic and detection technologies for the growing number of clinical challenges is rising each year. Here, we present a concise, yet didactic review on a new diagnostics frontier based on the detection of disease-related volatile organic compounds (VOCs) by means of nanomaterial-based sensors. Nanomaterials are ideal for such sensor arrays because they are easily fabricated, chemically versatile and can be integrated into currently available sensing platforms. Following a general introduction, we provide a brief description of the VOC-related diseases concept. Then, we focus on detection of VOC-related diseases by selective and crossreactive sensing approaches, through chemical, optical and mechanical transducers incorporating the most important classes of nanomaterials. Selected examples of the integration of nanomaterials into selective sensors and crossreactive sensor arrays are given. We conclude with a brief discussion on the integration possibilities of different types of nanomaterials into sensor arrays, and the expected outcomes and limitations.

Impact of Hemodialysis on Exhaled Volatile Organic Compounds in End-Stage Renal Disease: A Pilot Study

Published: May 2013

Authors: Assady, S.; Marom, O.; Hemli, M.; Ionescu, R.; Jeries, R.; Tisch, U.; Abassi, Z.; Haick, H.

Years: 2013

Published in: Nanomedicine, doi: 10.2217/nnm.13.85., 9(7), 1035-1045

AIM:

To demonstrate the feasibility of nanomaterial-based sensors for identifying patterns of exhaled volatile organic compound of end-stage renal disease (ESRD) and study the impact of hemodialysis (HD) on these patterns.

PATIENTS & METHODS:
Exhaled breath samples were collected from a group of 37 volunteers (26 ESRD HD patients; 11 healthy controls); a third of the samples were randomly blinded for determining the sensitivity/specificity of the method. Discriminant function analysis was used to build a model for discriminating ESRD patients and healthy controls (classification accuracy for blind samples: 80%), based on the signals of the nanomaterial sensors.

RESULTS & CONCLUSION:
The breath pattern of the ESRD patients approached the healthy pattern during the HD treatment, without reaching it completely. Gas chromatography/mass spectrometry identified four volatile organic compounds as potential ESRD biomarkers. Although this pilot study has yielded encouraging results, additional large-scale clinical studies are required to develop a fast, noninvasive breath test for monitoring HD adequacy in real time.
KEYWORDS:
breath test; carbon nanotube; dialysis adequacy; end-stage renal disease; gold nanoparticle; hemodialysis; sensor; volatile organic compound

Field Effect Transistors Based on Polycyclic Aromatic Hydrocarbons for the Detection and Classification of Volatile Organic Compounds

Published: April 2013

Authors: Bayn, A.; Feng, X.; Müllen, K.; Haick, H.

Years: 2013

Published in: Acs Appl. Mater. Interf., 5 (8), 3431−3440

We show that polycyclic aromatic hydrocarbon (PAH) based field effect transistor (FET) arrays can serve as excellent chemical sensors for the detection of volatile organic compounds (VOCs) under confounding humidity conditions. Using these sensors, w/o complementary pattern recognition methods, we study the ability of PAH-FET(s) to: (i) discriminate between aromatic and non-aromatic VOCs; (ii) distinguish polar and non-polar non-aromatic compounds; and to (iii) identify specific VOCs within the subgroups (i.e., aromatic compounds, polar non-aromatic compounds, non-polar non-aromatic compounds). We further study the effect of water vapor on the sensor array’s discriminative ability and derive patterns that are stable when exposed to different constant values of background humidity. Patterns based on different independent electronic features from an array of PAH-FETs may bring us one step closer to creating a unique fingerprint for individual VOCs in real-world applications in atmospheres with varying levels of humidity.

Effect of Functional Groups on the Sensing Properties of Silicon Nanowires toward Volatile Compounds

Published: March 2013

Authors: Wang, B.; Haick, H.

Years: 2013

Published in: Acs Appl. Mater. Interf., 5, 2289-2299

Molecular layers attached to a silicon nanowire field effect transistor (SiNW FET) can serve as antennas for signal transduction of volatile organic compounds (VOCs). Nevertheless, the mutual relationship between the molecular layers and VOCs is still a puzzle. In the present paper, we explore the effect of the molecular layer’s end (functional) groups on the sensing properties of VOCs. Toward this end, SiNW FETs were modified with tailor-made molecular layers that have the same backbone but differ in their end groups. Changes in the threshold voltage (ΔVth) and changes in the mobility (Δμh) were then recorded upon exposure to various VOCs. Model-based analysis indicates that the interaction between molecular layers and VOCs can be classified to three main scenarios: (a) dipole−dipole interaction between the molecular layer and the polar VOCs; (b) induced dipole−dipole interaction between the molecular layers and the nonpolar VOCs; and (c) molecular layer tilt as a result of VOCs diffusion. Based on these scenarios, it is likely that the electron-donating/withdrawing properties of the functional groups control the dipole moment orientation of the adsorbed VOCs and, as a result, determine the direction (or sign) of the ΔVth. Additionally, it is likely the diffusion of VOCs into the molecular layer, determined by the type of functional groups, is the main reason for the Δμh responses. The reported findings are expected to provide an efficient way to design chemical sensors that are based on SiNW FETs to nonpolar VOCs, which do not exchange carriers with the molecular layers.

A Nanomaterial-Based Breath Test for Distinguishing Gastric Cancer from Benign Gastric Conditions

Published: March 2013

Authors: Xu, Z. Q.; Broza, Y. Y.; Ionescu, R.; Tisch, U.; Ding, L.; Liu, H.; Song, Q.; Pan, Y.Y.; Xiong, F.; Gu, K.; Sun, G.; Chen, J.; Leja, M.; Haick, H.

Years: 2013

Published in: Br. J. Cancer, 108 (4), 941–950

BACKGROUND:

Upper digestive endoscopy with biopsy and histopathological evaluation of the biopsy material is the standard method for diagnosing gastric cancer (GC). However, this procedure may not be widely available for screening in the developing world, whereas in developed countries endoscopy is frequently used without major clinical gain. There is a high demand for a simple and non-invasive test for selecting the individuals at increased risk that should undergo the endoscopic examination. Here, we studied the feasibility of a nanomaterial-based breath test for identifying GC among patients with gastric complaints.

METHODS:
Alveolar exhaled breath samples from 130 patients with gastric complaints (37 GC/32 ulcers / 61 less severe conditions) that underwent endoscopy/biopsy were analyzed using nanomaterial-based sensors. Predictive models were built employing discriminant factor analysis (DFA) pattern recognition, and their stability against possible confounding factors (alcohol/tobacco consumption; Helicobacter pylori) was tested. Classification success was determined (i) using leave-one-out cross-validation and (ii) by randomly blinding 25% of the samples as a validation set. Complementary chemical analysis of the breath samples was performed using gas chromatography coupled with mass spectrometry.

RESULTS:
Three DFA models were developed that achieved excellent discrimination between the subpopulations: (i) GC vs benign gastric conditions, among all the patients (89% sensitivity; 90% specificity); (ii) early stage GC (I and II) vs late stage (III and IV), among GC patients (89% sensitivity; 94% specificity); and (iii) ulcer vs less severe, among benign conditions (84% sensitivity; 87% specificity). The models were insensitive against the tested confounding factors. Chemical analysis found that five volatile organic compounds (2-propenenitrile, 2-butoxy-ethanol, furfural, 6-methyl-5-hepten-2-one and isoprene) were significantly elevated in patients with GC and/or peptic ulcer, as compared with less severe gastric conditions. The concentrations both in the room air and in the breath samples were in the single p.p.b.v range, except in the case of isoprene.

CONCLUSION:
The preliminary results of this pilot study could open a new and promising avenue to diagnose GC and distinguish it from other gastric diseases. It should be noted that the applied methods are complementary and the potential marker compounds identified by gas-chromatography/mass spectrometry are not necessarily responsible for the differences in the sensor responses. Although this pilot study does not allow drawing far-reaching conclusions, the encouraging preliminary results presented here have initiated a large multicentre clinical trial to confirm the observed patterns for GC and benign gastric conditions

Oxide-Free Hybrid Silicon Nanowires: from Fundamentals to Applied Nanotechnology

Published: February 2013

Authors: Bashouti, M. Y.; Sardashti, K.; Schmitt, S.W.; Pietsch, M.; Ristein, J.; Haick, H.; Christiansen, S.

Years: 2013

Published in: Prog. Surf. Sci., 88, 39–60

The ability to control physical properties of silicon nanowires (Si NWs) by designing their surface bonds is important for their applicability in devices in the areas of nano-electronics, nano-photonics, including photovoltaics and sensing. In principle a wealth of different molecules can be attached to the bare Si NW surface atoms to create e.g. Si–O, Si–C, Si–N, etc. to mention just the most prominent ones. Si–O bond formation, i.e. oxidation usually takes place automatically as soon as Si NWs are exposed to ambient conditions and this is undesired is since a defective oxide layer (i.e. native silicon dioxide – SiO2) can cause uncontrolled trap states in the band gap of silicon. Surface functionalization of Si NW surfaces with the aim to avoid oxidation can be carried out by permitting e.g. Si–C bond formation when alkyl chains are covalently attached to the Si NW surfaces by employing a versatile two-step chlorination/alkylation process that does not affect the original length and diameter of the NWs. Termination of Si NWs with alkyl molecules through covalent Si–C bonds can provide long term stability against oxidation of the Si NW surfaces. The alkyl chain length determines the molecular coverage of Si NW surfaces and thus the surface energy and next to simple Si–C bonds even bond types such as C C and C C can be realized. When integrating differently functionalized Si NWs in functional devices such as field effect transistors (FETs) and solar cells, the physical properties of the resultant devices vary.

Volatile Organic Compounds of Lung Cancer and Possible Biochemical Pathways

Published: November 2012

Authors: Hakim, M.; Broza, Y. Y.; Barash, O.; Peled, N.; Phillips, M.; Amann, A.; Haick, H.

Years: 2012

Published in: Chem. Rev., 112 (11), 5949–5966

1. Introduction
2. Volatile Organic Compounds of Lung Cancer
3. Biochemical Pathways of Volatile Organic Compounds of Lung Cancer
3.1. Hydrocarbons
3.2. Alcohols
3.3. Aldehydes
3.4. Ketones
3.5. Esters
3.6. Nitriles
3.7. Aromatic Compounds
4. Conclusions and Outlook

Non-invasive Breath Analysis of Pulmonary Nodules

Published: October 2012

Authors: Peled, N.; Hakim, M.; Bunn, P.,A.; Miller, Y.E.; Kennedy, T.C.; Mattei, J.; Mitchell, J.D.; Hirsch, F. R.; Haick, H.

Years: 2012

Published in: J. Thorac. Oncol., 7 (10), 1528-1533

INTRODUCTION:
The search for non-invasive diagnostic methods of lung cancer (LC) has led to new avenues of research, including the exploration of the exhaled breath. Previous studies have shown that LC can, in principle, be detected through exhaled-breath analysis. This study evaluated the potential of exhaled-breath analysis for the distinction of benign and malignant pulmonary nodules (PNs).
METHODS:
Breath samples were taken from 72 patients with PNs in a prospective trial. Profiles of volatile organic compounds were determined by (1) gas chromatography/mass spectrometry (GC-MS) combined with solid-phase microextraction and (2) a chemical nanoarray.
RESULTS:
Fifty-three PNs were malignant and 19 were benign with similar smoking histories and comorbidities. Nodule size (mean ± SD) was 2.7 ± 1.7 versus 1.6 ± 1.3 cm (p = 0.004), respectively. Within the malignant group, 47 were non-small-cell lung cancer and six were small-cell lung cancer. Thirty patients had early-stage disease and 23 had advanced disease. Gas chromatography/mass spectrometry analysis identified a significantly higher concentration of 1-octene in the breath of LC, and the nanoarray distinguished significantly between benign versus malignant PNs (p < 0.0001; accuracy 88 ± 3%), between adeno- and squamous-cell carcinomas [LINE SEPARATOR](p < 0.0001; 88 ± 3%) and between early stage and advanced disease (p < 0.0001; 88 ± 2%).
CONCLUSIONS:
In this pilot study, breath analysis discriminated benign from malignant PNs in a high-risk cohort based on LC-related volatile organic compound profiles. Furthermore, it discriminated adeno- and squamous-cell carcinoma and between early versus advanced disease. Further studies are required to validate this noninvasive approach, using a larger cohort of patients with PNs detected by computed tomography.

Polycyclic Aromatic Hydrocarbon for the Detection of Nonpolar Analytes under Counteracting Humidity Conditions

Published: September 2012

Authors: Bachar, N.; Mintz, L.; Zilberman, Y.; Ionescu, R.; Feng, X.; Müllen, K.; Haick, H.

Years: 2012

Published in: Acs Appl. Mater. Interf., 4 (9), 4960–4965

Real-world samples contain reducing and oxidizing chemical agents as well as large and small (bio)molecules, which are polar or nonpolar in nature. Sensing nonpolar analytes, which is of paramount importance for a wide variety of applications, is generally more difficult to achieve than sensing polar analytes. Here, we report on empirical observations of a unique polycyclic aromatic hydrocarbon derivative, referred as PAH-A, whose structure has a triangular-shaped aromatic core (with a carbon number of 60) and contains hydrophobic mesogens terminated with hydrophobic alkyl chains. We show that films made of PAH-A enable excellent sensitivity to nonpolar analytes, compared to polar analytes, in a setting of 5–40% counteracting relative humidity. This finding is based on monitoring the changes in the physical/optical properties of thin PAH-A films upon exposure to nonpolar and polar analytes, by means of quartz crystal microbalance and spectroscopic ellipsometry measurements. A comparison with other polycyclic aromatic hydrocarbon derivatives with different cores or organic functionalities is provided and discussed.

Field-Effect Transistors Based on Silicon Nanowire Arrays: Effect of the Good and the Bad Silicon Nanowires

Published: August 2012

Authors: Wang, B.; Stelzner, T.; Dirawi, R.; Assad, O.; Shehada, N.; Christiansen, S.; Haick, H.

Years: 2012

Published in: Acs Appl. Mater. Interf., 4, 4251−4258

Aligned arrays of silicon nanowires (aa-Si NWs) allow the exploitation of Si NWs in a scalable way. Previous studies explored the influence of the Si NWs’ number, doping density, and diameter on the related electrical performance. Nevertheless, the origin of the observed effects still not fully understood. Here, we aim to provide an understanding on the effect of channel number on the fundamental parameters of aa-Si NW field effect transistors (FETs). Toward this end, we have fabricated and characterized 87 FET devices with varied number of Si NWs, which were grown by chemical vapor deposition with gold catalyst. The results show that FETs with Si NWs above a threshold number (n > 80) exhibit better device uniformity, but generally lower device performance, than FETs with lower number of Si NWs (3 ≤ n < 80). Complementary analysis indicates that the obtained discrepancies could be explained by a weighted contribution of two main groups of Si NWs: (i) a group of gold-free Si NWs that exhibit high and uniform electrical characteristics; and (ii) a group of gold-doped Si NWs that exhibit inferior electrical characteristics. These findings are validated by a binomial model that consider the aa-Si NW FETs via a weighted combination of FETs of individual Si NWs. Overall, the obtained results suggest that the criterions used currently for evaluating the device performance (e.g., uniform diameter, length, and shape of Si NWs) do not necessarily guarantee uniform or satisfying electrical characteristics, raising the need for new growth processes and/or advanced sorting techniques of electrically homogeneous Si NWs.

Detection of Volatile Organic Compounds in Cattle Naturally Infected with Mycobacterium Bovis

Published: August 2012

Authors: Peled, N.; Ionescu, R.; Nol, P.; Barash, O.; McCollum, M.; VerCauterenc, K.; Koslow, M.; Stahl, R.; Rhyan, J.; Haick, H.

Years: 2012

Published in: Sens. Actuat. B, 171– 172, 588– 594

We report here on a novel methodology in detecting Mycobacterium bovis (M. bovis) infection in cattle, based on identifying unique volatile organic compounds (VOCs) or a VOC profile in the breath of cattle. The study was conducted on an M. bovis-infected dairy located in southern Colorado, USA, and on two tuberculosis-free dairies from northern Colorado examined as negative controls. Gas-chromatography/mass-spectrometry analysis revealed the presence of 2 VOCs associated with M. bovis infection and 2 other VOCs associated with the healthy state in the exhaled breath of M. bovis-infected and not infected animals, yielding distinctly different VOC patterns for the two study groups. Based on these results, a nanotechnology-based array of sensors was then tailored for detection of M. bovis-infected cattle via breath. Our system successfully identified all M. bovis-infected animals, while 21% of the not infected animals were classified as M. bovis-infected. This technique could form the basis for a real-time cattle monitoring system that allows efficient and non-invasive screening for new M. bovis infections on dairy farms.

Effect of Perforation on the Sensing Properties of Monolayer-Capped Metallic Nanoparticle Films

Published: July 2012

Authors: Segev-Bar, M.; Shuster, G.; Haick, H.

Years: 2012

Published in: J. Phys. Chem. C., 116, 15361−15368

We report on the effect of perforation within a monolayer-capped metallic nanoparticle (MCNP) film on sensing of volatile organic compounds (VOCs) and water molecules. Our results show that continuous MCNP film exhibits positive responses on exposure to VOCs and to water, consistent with the swelling and dielectric sensing mechanisms. In contrast, perforated films exhibit positive responses on exposure to VOCs but a high-magnitude negative response on exposure to high levels of water. The negative responses were higher by at least 1 order of magnitude compared with the positive responses. The results are explained in terms of ionization of condensed water and/or SiO2 sites in MCNP-free domains under applied voltage, side-by-side with the tunneling mechanism within the MCNP domains. The controlled morphology afforded by MCNP assemblies, combined with the existence of multiple sensing mechanisms under real-world humidity conditions, would enable a host of new fundamental and applied opportunities.

Structural and Electrical Properties of Single Ga/ZnO Nanofibers Synthesized by Electrospinning

Published: July 2012

Authors: Shmueli, Y.; Shter, E.G.; Assad, O.; Haick, H.; Sonntag. P.; Ricoux, P.; Grader, S.G.

Years: 2012

Published in: J. Mater. Res., 27 (13), 1672-1679

Nanofibers (NFs) of Ga-doped ZnO (GZO) were prepared by electrospinning of polymer–salts solution. Sintering profiles reported in the literature led to loss of the fibrous structure. Hence, the morphology, thermal stability, and phase composition of green and sintered fibers were investigated as function of sintering conditions to elucidate this degradation process. Optimal results were obtained at 400 °C for 30 min. This low temperature sintering of GZO fibers has not been previously reported. The fibers were porous with a significant surface area, making it possible to test their sensitivity to environmental changes. In particular, the response of the GZO NFs to changes in humidity was demonstrated for the first time. The electrical and sensing properties of single NFs prepared at these conditions were studied using a field-effect transistor mode.

Hybrids of Organic Molecules and Flat, Oxide-Free Silicon: High- Density Monolayers, Electronic Properties, and Functionalization

Published: July 2012

Authors: Li, Y.; Calder, S.; Yaffe, O.; Cahen, D.; Haick, H.; Kronik, L.; Zuilhof, H.

Years: 2012

Published in: Langmuir, 28, 9920-9929

Since the first report of Si–C bound organic monolayers on oxide-free Si almost two decades ago, a substantial amount of research has focused on studying the fundamental mechanical and electronic properties of these Si/molecule surfaces and interfaces. This feature article covers three closely related topics, including recent advances in achieving high-density organic monolayers (i.e., atomic coverage >55%) on oxide-free Si(111) substrates, an overview of progress in the fundamental understanding of the energetics and electronic properties of hybrid Si/molecule systems, and a brief summary of recent examples of subsequent functionalization on these high-density monolayers, which can significantly expand the range of applicability. Taken together, these topics provide an overview of the present status of this active area of research.

Spray-Coating Route for Highly Aligned and Large-Scale Arrays of Nanowires

Published: June 2012

Authors: Assad, O.; Leshansky, M.A.; Wang, B.; Stelzner, T.; Christiansen, S.; Haick, H.

Years: 2012

Published in: ACS Nano., 6 (6), 4702–4712

Technological implementation of nanowires (NWs) requires these components to be organized with controlled orientation and density on various substrates. Here, we report on a simple and efficient route for the deposition of highly ordered and highly aligned NW arrays on a wide range of receiver substrates, including silicon, glass, metals, and flexible plastics with controlled density. The deposition approach is based on spray-coating of a NW suspension under controlled conditions of the nozzle flow rate, droplet size of the sprayed NWs suspension, spray angle, and the temperature of the receiver substrate. The dynamics of droplet generation is understood by a combined action of shear forces and capillary forces. Provided that the size of the generated droplet is comparable to the length of the single NW, the shear-driven elongation of the droplets results presumably in the alignment of the confined NW in the spraying direction. Flattening the droplets upon their impact with the substrate yields fast immobilization of the spray-aligned NWs on the surface due to van der Waals attraction. The availability of the spray-coating technique in the current microelectronics technology would ensure immediate implementation in production lines, with minimal changes in the fabrication design and/or auxiliary tools used for this purpose.

Interactive Effect of Hysteresis and Surface Chemistry on Gated Silicon Nanowire Gas Sensors

Published: May 2012

Authors: Paska, Y.; Haick, H.

Years: 2012

Published in: Acs Appl. Mater. Interf., 4, 2604-2617

Gated silicon nanowire gas sensors have emerged as promising devices for chemical and biological sensing applications. Nevertheless, the performance of these devices is usually accompanied by a “hysteresis” phenomenon that limits their performance under real-world conditions. In this paper, we use a series of systematically changed trichlorosilane-based organic monolayers to study the interactive effect of hysteresis and surface chemistry on gated silicon nanowire gas sensors. The results show that the density of the exposed or unpassivated Si–OH groups (trap states) on the silicon nanowire surface play by far a crucial effect on the hysteresis characteristics of the gated silicon nanowire sensors, relative to the effect of hydrophobicity or molecular density of the organic monolayer. Based on these findings, we provide a tentative model-based understanding of (i) the relation between the adsorbed organic molecules, the hysteresis, and the related fundamental parameters of gated silicon nanowire characteristics and of (ii) the relation between the hysteresis drift and possible screening effect on gated silicon nanowire gas sensors upon exposure to different analytes at real-world conditions. The findings reported in this paper could be considered as a launching pad for extending the use of the gated silicon nanowire gas sensors for discriminations between polar and nonpolar analytes in complex, real-world gas mixtures.

Gold Nanoparticle Sensors for Detecting Chronic Kidney Disease and Disease Progression

Published: May 2012

Authors: Marom, O.; Nakhoul, F.; Tisch, U.; Shiban, A.; Abassi, Z.; Haick, H.

Years: 2012

Published in: Nanomedicine (Lond)., 7 (5), 639-650

AIM:
To study the feasibility of a novel nanomedical method that utilizes breath testing for identifying chronic kidney disease (CKD) and disease progression.
MATERIALS & METHODS:
Exhaled breath samples were collected from 62 volunteers. The breath samples were analyzed using sensors based on organically functionalized gold nanoparticles, combined with support vector machine analysis. Sensitivity and specificity with reference to CKD patient classification according to estimated glomerular filtration rate were determined using cross-validation. The chemical composition of the breath samples was studied using gas chromatography linked with mass spectrometry.
RESULTS:
A combination of two to three gold nanoparticles sensors provided good distinction between early-stage CKD and healthy states (accuracy of 79%) and between stage 4 and 5 CKD states (accuracy of 85%). A single sensor provided a distinction between early and advanced CKD (accuracy of 76%). Several substances in the breath were identified and could be associated with CKD-related biochemical processes or with the accumulation of toxins through kidney function loss.
CONCLUSION:
Breath testing using gold nanoparticle sensors holds future potential as a cost-effective, fast and reliable diagnostic test for early detection of CKD and monitoring of disease progression.

Volatile Organic Compounds in Exhaled Breath as Biomarkers for the Early Detection and Screening of Lung Cancer

Published: May 2012

Authors: Tisch, U.; Billan, S.; Ilouze, M.; Phillips, M.; Peled, N.; Haick, H.

Years: 2012

Published in: CML – Lung Cancer, 5 (4), 107–117

The article offers information on detection and screening of lung cancer. Staging of this disease can be classified according to the tumor, node and metastasis (TNM). It notes that most lung cancers originate from epithelial cells, and can be classified as small-cell lung carcinoma (SCLC), squamous cell carcinoma or large cell carcinoma. Lung cancer can be diagnosed through computed tomography (CT) and positron emission tomography (PET).

Molecular Gating of Silicon Nanowire Field-Effect Transistors with Nonpolar Analytes

Published: January 2012

Authors: Paska, Y.; Stelzner, T.; Assad, O.; Tisch, U.; Christiansen, S.; Haick, H.

Years: 2012

Published in: ACS Nano., 6 (1), 335-345

Silicon nanowire field-effect transistors (Si NW FETs) have been used as powerful sensors for chemical and biological species. The detection of polar species has been attributed to variations in the electric field at the conduction channel due to molecular gating with polar molecules. However, the detection of nonpolar analytes with Si NW FETs has not been well understood to date. In this paper, we experimentally study the detection of nonpolar species and model the detection process based on changes in the carrier mobility, voltage threshold, off-current, off-voltage, and subthreshold swing of the Si NW FET. We attribute the detection of the nonpolar species to molecular gating, due to two indirect effects: (i) a change in the dielectric medium close to the Si NW surface and (ii) a change in the charged surface states at the functionality of the Si NW surface. The contribution of these two effects to the overall measured sensing signal is determined and discussed. The results provide a launching pad for real-world sensing applications, such as environmental monitoring, homeland security, food quality control, and medicine.

International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 Report

Published: January 2012

Authors: Field, J.K.; Smith, R.A.; Aberle, D.R.; Oudkerk, M.; Baldwin, D.R.; Yankelevitz, D.; Pedersen, J.H.; Swanson, S.J.; Travis, W.D.; Wisbuba, I.I.; Noguchi, M.; Mulshine, J.L.; IASLC CT Screening Workshop 2011 Participants

Years: 2012

Published in: J. Thorac. Oncol., 7,10-19

The International Association for the Study of Lung Cancer (IASLC) Board of Directors convened a computed tomography (CT) Screening Task Force to develop an IASLC position statement, after the National Cancer Institute press statement from the National Lung Screening Trial showed that lung cancer deaths fell by 20%. The Task Force’s Position Statement outlined a number of the major opportunities to further improve the CT screening in lung cancer approach, based on experience with cancer screening from other organ sites.The IASLC CT Screening Workshop 2011 further developed these discussions, which are summarized in this report. The recommendation from the workshop, and supported by the IASLC Board of Directors, was to set up the Strategic CT Screening Advisory Committee (IASLC-SSAC). The Strategic CT Screening Advisory Committee is currently engaging professional societies and organizations who are stakeholders in lung cancer CT screening implementation across the globe, to focus on delivering guidelines and recommendations in six specific areas: (i) identification of high-risk individuals for lung cancer CT screening programs; (ii) develop radiological guidelines for use in developing national screening programs; (iii) develop guidelines for the clinical work-up of “indeterminate nodules” resulting from CT screening programmers; (iv) guidelines for pathology reporting of nodules from lung cancer CT screening programs; (v) recommendations for surgical and therapeutic interventions of suspicious nodules identified through lung cancer CT screening programs; and (vi) integration of smoking cessation practices into future national lung cancer CT screening programs.

Charge Transport Across Metal/Molecular (alkyl) Monolayer-Si Junctions is Dominated by the LUMO Level

Published: January 2012

Authors: Yaffe, O.; Qi, Y.; Scheres, L.; Puniredd, S. R.; Segev, L.; Ely, T.; Haick, H.; Zuilhof, H.; Vilan, A.; Kronik, L.; Kahn, A.; Cahen, D.

Years: 2012

Published in: Phys. Rev. B, 85, 045433/1-045433/8

We compare the charge transport characteristics of heavy-doped p++- and n++-Si-alkyl chain/Hg junctions. Based on negative differential resistance in an analogous semiconductor-inorganic insulator/metal junction we suggest that for both p++- and n++-type junctions, the energy difference between the Fermi level and lowest unoccupied molecular orbital (LUMO), i.e., electron tunneling, controls charge transport. This conclusion is supported by results from photoelectron spectroscopy (ultraviolet photoemission spectroscopy, inverse photoelectron spectroscopy, and x-ray photoemission spectroscopy) for the molecule-Si band alignment at equilibrium, which clearly indicate that the energy difference between the Fermi level and the LUMO is much smaller than that between the Fermi level and the highest occupied molecular orbital (HOMO). Furthermore, the experimentally determined Fermi level – LUMO energy difference, agrees with the non-resonant tunneling barrier height, deduced from the exponential length attenuation of the current.

Molecular Gating of Silicon Nanowire Field-Effect Transistors with Nonpolar Analytes

Published: December 2011

Authors: Paska, Y.; Stelzner, T.; Assad, O.; Tisch, U.; Christiansen, S.; Haick, H.

Years: 2011

Published in: ACS Nano., 6 (1), 335-345

Silicon nanowire field-effect transistors (Si NW FETs) have been used as powerful sensors for chemical and biological species. The detection of polar species has been attributed to variations in the electric field at the conduction channel due to molecular gating with polar molecules. However, the detection of nonpolar analytes with Si NW FETs has not been well understood to date. In this paper, we experimentally study the detection of nonpolar species and model the detection process based on changes in the carrier mobility, voltage threshold, off-current, off-voltage, and subthreshold swing of the Si NW FET. We attribute the detection of the nonpolar species to molecular gating, due to two indirect effects: (i) a change in the dielectric medium close to the Si NW surface and (ii) a change in the charged surface states at the functionality of the Si NW surface. The contribution of these two effects to the overall measured sensing signal is determined and discussed. The results provide a launching pad for real-world sensing applications, such as environmental monitoring, homeland security, food quality control, and medicine.

Detection of Asymptomatic Nigrostriatal Dopaminergic Leison in Rats by Exhaled Air Analysis Using Carbon Nanotube Sensors

Published: December 2011

Authors: Tisch, U.; Aluf, Y.; Ionescu, R.; Nakhleh, K. M.; Bassal, R.; Axelrod, N.; Robertman, D.; Tessler, Y.; Finberg, J.P.M.; Haick, H.

Years: 2011

Published in: ACS Chem. Neurosci., 3, 161-166

The ante-mortem diagnosis of Parkinson’s disease (PD) still relies on clinical symptoms. Biomarkers could in principle be used for the early detection of PD-related neuronal damage, but no validated, inexpensive, and simple biomarkers are available yet. Here we report on the breath-print of presymptomatic PD in rats, using a model with 50% lesion of dopaminergic neurons in substantia nigra. Exhaled breath was collected from 19 rats (10 lesioned and 9 sham operated) and analyzed using organically functionalized carbon nanotube sensors. Discriminant factor analysis detected statistically significant differences between the study groups and a classification accuracy of 90% was achieved using leave-one-out cross-validation. The sensors’ breath-print was supported by determining statistically significant differences of several volatile organic compounds in the breath of the lesioned rats and the sham operated rats, using gas chromatography combined with mass spectrometry. The observed breath-print shows potential for cost-effective, fast, and reliable early PD detection.

Probing the Electrostatics of Self-Assembled Monolayers by Means of Beveled Metal-Oxide-Semiconductor Structures

Published: December 2011

Authors: Kornblum, L.; Paska, Y.; Rothschild, A.J.; Haick, H.; Eizenberg, M.

Years: 2011

Published in: Appl. Phys. Lett., 99, 233508/1-233508/3

A method is proposed for characterization of the electrostatics of self-assembledmonolayers(SAMs). The method is based on the extraction of the metal’s effective work function in metal-oxide-semiconductor capacitors, where the SAM is positioned at the metal-oxide interface. Hexyltrichlorosilane molecules assembled on SiO2 are used as a model system for this method. A band offset of 0.5 ± 0.15 eV is observed in the SAM sample when compared to a reference with no molecules. Spectroscopy is employed to confirm the presence of silane anchoring groups after metal deposition.

Effect of Humidity on NanoParticle-Based Chemiresistors: A Comparison between Synthetic and Real-World Samples

Published: November 2011

Authors: Konvalina, G.; Haick, H.

Years: 2001

Published in: Acs Appl. Mater. Interf., 4, 317-325

Chemiresistors based on metal monolayer-capped nanoparticles (MCNPs) are promising candidates for fast, inexpensive, and portable tracing of (bio)chemical species in the gas phase. However, the sensitivity of such sensors to humidity is problematic, limiting their reliable and reproducible application in real-world environmental conditions. In this work, we employed a compensation method to explore the effect of humidity on a single MCNP chemiresistor as well as on an array of MCNP sensors used to analyze either synthetic or real-world samples. We show that an array of MCNP chemiresistors is able to precisely detect and estimate subtle concentrations of (mixtures of) volatile organic compounds (VOCs) under variable backgrounds of 2–83% relative humidity (RH) only after humidity compensation. Humidity effects were also tested in two clinical trials aimed at detecting prostate cancer and breast cancer through exhaled breath analysis. Analysis of the results showed improved cancer detection capabilities as a result of RH compensation, though less substantial than the impact of RH compensation on synthetic samples. This outcome is attributed to one – or a combination – of the following effects: (i) the RH variance was smaller in the breath samples than that in the synthetic samples; (ii) the VOC composition in the breath samples is less controlled than the synthetic samples; and (iii) the responses to small polar VOCs and water are not necessarily additive in breath samples. Ultimately, the results presented here could assist the development of a cost-effective, low-power method for widespread detection of VOCs in real-world applications, such as breath analysis, as well as for environmental, security, and food applications.

Classification of Lung Cancer Histology by Gold Nanoparticle Sensors

Published: October 2011

Authors: Barash, O.; Peled, N.; Tisch, U.; Bunn, P. A. Jr.; Hirsch, F. R.; Haick, H.

Years: 2011

Published in: Nanomedicine (NY, US)., 8(5), 580-589

We propose a nanomedical device for the classification of lung cancer (LC) histology. The device profiles volatile organic compounds (VOCs) in the headspace of (subtypes of) LC cells, using gold nanoparticle (GNP) sensors that are suitable for detecting LC-specific patterns of VOC profiles, as determined by gas chromatography–mass spectrometry analysis. Analyzing the GNP sensing signals by support vector machine allowed significant discrimination between (i) LC and healthy cells; (ii) small cell LC and non–small cell LC; and between (iii) two subtypes of non–small cell LC: adenocarcinoma and squamous cell carcinoma. The discriminative power of the GNP sensors was then linked with the chemical nature and composition of the headspace VOCs of each LC state. These proof-of-concept findings could totally revolutionize LC screening and diagnosis, and might eventually allow early and differential diagnosis of LC subtypes with detectable or unreachable lung nodules.

Detection of Multiple Sclerosis from Exhaled Breath Using Bilayers of Polycyclic Aromatic Hydrocarbons and Single-Wall Carbon Nanotubes

Published: September 2011

Authors: Ionescu, R.; Broza, Y. Y.; Shaltieli, H.; Sadeh, D.; Zilberman, Y.; Feng, X.; Lejbkowicz, I.; Glass-Marmor, L.; Müllen, K.; Miller, A.; Haick, H.

Years: 2011

Published in: ACS Chem. Neurosci., 2 (12), 687–693

A cross-reactive array of polycyclic aromatic hydrocarbons and single wall carbon nanotube bilayers was designed for the detection of volatile organic compounds (tentatively, hexanal and 5-methyl-undecane) that identify the presence of disease in the exhaled breath of patients with multiple sclerosis. The sensors showed excellent discrimination between hexanal, 5-methyl-undecane, and other confounding volatile organic compounds. Results obtained from a clinical study consisting of 51 volunteers showed that the sensors could discriminate between multiple sclerosis and healthy states from exhaled breath samples with 85.3% sensitivity, 70.6% specificity, and 80.4% accuracy. These results open new frontiers in the development of a fast, noninvasive, and inexpensive medical diagnostic tool for the detection and identification of multiple sclerosis. The results could serve also as a launching pad for the discrimination between different subphases or stages of multiple sclerosis as well as for the identification of multiple sclerosis patients who would respond well to immunotherapy.

Utility of Resistance and Capacitance Response in Sensors Based on Monolayer-Capped Metal Nanoparticles

Published: July 2011

Authors: Shuster, G.; Baltianski, S.; Tsur, Y.; Haick, H.

Years: 2011

Published in: J. Phys. Chem. Lett, 2 (15), 1912–1916

We investigate the utility of resistance and capacitance responses, as derived by impedance spectroscopy, in well-controlled and real-world applications of monolayer-capped metal nanoparticle (MCNP) sensors. Exposure of the MCNP films to well-controlled analytes showed stable sensing responses and low baseline drift of the pertinent capacitance signals, when compared with equivalent resistance signals. In contrast, exposure of the MCNP films to breath of chronic kidney disease patients under dialysis, as a representative example to real-world multicomponent mixtures, showed low baseline drift but relatively scattered signals when compared with the equivalent resistance response. We ascribe these discrepancies to the level and fluctuating concentration of water molecules in the real-world samples.

Enhanced Sensing of Nonpolar Volatile Organic Compounds by Silicon Nanowire Field Effect Transistors

Published: June 2011

Authors: Paska, Y.; Stelzner, T.; Christiansen, S.; Haick, H.

Years: 2011

Published in: ACS Nano., 5 (7), 5620–5626

Silicon nanowire field effect transistors (Si NW FETs) are emerging as powerful sensors for direct detection of biological and chemical species. However, the low sensitivity of the Si NW FET sensors toward nonpolar volatile organic compounds (VOCs) is problematic for many applications. In this study, we show that modifying Si NW FETs with a silane monolayer having a low fraction of Si–O–Si bonds between the adjacent molecules greatly enhances the sensitivity toward nonpolar VOCs. This can be explained in terms of an indirect sensor–VOC interaction, whereby the nonpolar VOC molecules induce conformational changes in the organic monolayer, affecting (i) the dielectric constant and/or effective dipole moment of the organic monolayer and/or (ii) the density of charged surface states at the SiO2/monolayer interface. In contrast, polar VOCs are sensed directly via VOC-induced changes in the Si NW charge carriers, most probably due to electrostatic interaction between the Si NW and polar VOCs. A semiempirical model for the VOC-induced conductivity changes in the Si NW FETs is presented and discussed.

Arrays of Chemisensitive Monolayer-Capped Metallic Nanoparticles for Diagnostic Breath Testing

Published: May 2011

Authors: Tisch, U.; Haick, H.

Years: 2011

Published in: Rev. Chem. Eng., 26,171-179

Arrays of cross-reactive sensors are well suited to detect subtle changes in clinical samples resulting from internal diseases. Monolayer-capped metallic nanoparticles (MCNPs) are ideal base materials for such sensor arrays because they are chemically versatile, easily fabricated, and readily integrated into chemiresistive sensing platforms using microelectrodes. In this review, we present the main concepts and approaches related to the use of MCNPs in chemiresistors and show their applicability to exhaled breath testing, which is a new non-invasive frontier of medical diagnostics.

Diagnosis of Head-and-Neck Cancer from Exhaled Breath

Published: April 2011

Authors: Hakim, M.; Billan, S.; Tisch, U.; Peng, G.; Dvrokind, I.; Marom, O.; Abdah- Brotnyak, R.; Kuten, A.; Haick, H.

Years: 2011

Published in: Br. J. Cancer, 104, 1649–1655

BACKGROUND:
Head-and-neck cancer (HNC) is the eighth most common malignancy worldwide. It is often diagnosed late due to a lack of screening methods and overall cure is achieved in <50% of patients. Head-and-neck cancer sufferers often develop a second primary tumour that can affect the entire aero-digestive tract, mostly HNC or lung cancer (LC), making lifelong follow-up necessary.

METHODS:
Alveolar breath was collected from 87 volunteers (HNC and LC patients and healthy controls) in a cross-sectional clinical trial. The discriminative power of a tailor-made Nanoscale Artificial Nose (NA-NOSE) based on an array of five gold nanoparticle sensors was tested, using 62 breath samples. The NA-NOSE signals were analysed to detect statistically significant differences between the sub-populations using (i) principal component analysis with ANOVA and Student’s t-test and (ii) support vector machines and cross-validation. The identification of NA-NOSE patterns was supported by comparative analysis of the chemical composition of the breath through gas chromatography in conjunction with mass spectrometry (GC-MS), using 40 breath samples.

RESULTS:
The NA-NOSE could clearly distinguish between (i) HNC patients and healthy controls, (ii) LC patients and healthy controls, and (iii) HNC and LC patients. The GC-MS analysis showed statistically significant differences in the chemical composition of the breath of the three groups.

CONCLUSION:
The presented results could lead to the development of a cost-effective, fast, and reliable method for the differential diagnosis of HNC that is based on breath testing with an NA-NOSE, with a future potential as screening tool.

Catalyst-Free Functionalization for Versatile Modification of Non-Oxidized Silicon Structures

Published: March 2011

Authors: Puniredd, S. R.; Assad, O.; Stelzner, T.; Christiansen, S.; Haick, H.

Years: 2011

Published in: Langmuir, 27 (8), 4764–4771

Here, we report on a simple, catalyst-free route for obtaining highly versatile subsequent functionalization on Si nanowires and Si(111) substrates. The versatility of this approach allows subsequent functionalization not only for organic species but also for inorganic (nanomaterial) species. The method has the advantage of controlling the density of reactive cross-linkers without affecting the stability of the Si samples and without having metallic (or catalyst) residues on the surface. This method also allows formation of monolayers with a variety of termination groups and is expected to open up a wide range of opportunities for producing stable molecule-based (opto)electronic and (bio)sensing devices. Immobilization of inorganic nanomaterial on the Si samples offers advanced opportunities in molecular switches, (bio)sensors, molecular scale memory, and Si-based nanoelectronic devices.

Classification of Breast Cancer Precursors through Exhaled Breath, Breast Cancer Research and Treatment

Published: December 2010

Authors: Shuster, G.; Gallimidi, Z.; Reiss, A. H.; Dovgolevsky, E.; Billan, S.; Abdah- Brotnyak, R.; Kuten, A.; Engel, A.; Shiban, A.; Tisch, U.; Haick, H.

Years: 2010

Published in: Breast Cancer Res. Treat., 126, 791-796

Certain benign breast diseases are considered to be precursors of invasive breast cancer. Currently available techniques for diagnosing benign breast conditions lack accuracy. The purpose of this study was to deliver a proofof-concept for a novel method that is based on breath testing to identify breast cancer precursors. Within this context, the authors explored the possibility of using exhaled alveolar breath to identify and distinguish between benign breast conditions, malignant lesions, and healthy states, using a small-scale, case-controlled, cross-sectional clinical trial. Breath samples were collected from 36 volunteers and were analyzed using a tailor-made nanoscale artificial NOSE (NA-NOSE). The NA-NOSE signals were analyzed using two independent methods: (i) principal component analysis, ANOVA and Student’s t-test and (ii) support vector machine analysis to detect statistically significant differences between the sub-populations. The NA-NOSE could distinguish between all studied test populations. Breath testing with a NA-NOSE holds future potential as a cost-effective, fast, and reliable diagnostic test for breast cancer risk factors and precursors, with possible future potential as screening method.

Nanomaterials for Cross- Reactive Sensor Arrays

Published: October 2010

Authors: Tisch, U.; Haick, H.

Years: 2010

Published in: Bull. MRS., 35, 797-803

Arrays of cross-reactive sensors for the detection of multi-component chemical and biological agents have been actively developed during the past two decades. The rapid progress in this fi eld has been driven by the need for fast online detection of a wide range of chemical and biological compounds and mixtures in different branches of industry and in medicine. Nanomaterials are ideal base materials for such sensor arrays because they are chemically versatile, can easily be fabricated, and can be integrated into existing sensing platforms to increase the sensitivity to the target agents. We present a concise though non-exhaustive didactic review of the main concepts and approaches related to the use of nanomaterials in cross-reactive sensor arrays. We focus on electronic transducers incorporating the most important classes of nanomaterials: molecularly modifi ed metal nanoparticles, metal oxide nanoparticles, carbon nanotubes, and semiconducting nanowires. Selected examples of their integration into sensors and sensor arrays are given. We conclude with a brief discussion of the possibilities that the integration of the different types of nanomaterials into sensor arrays offer and the expected limitations.

Carbon Nanotube/ Hexa-peri- hexabenzocoronene Bilayers for Discrimination Between Nanopolar Volatile Organic Compounds of Cancer and Humid Atmospheres

Published: October 2010

Authors: Zilberman, Y.; Tisch, U.; Shuster, G.; Pisula, W.; Feng, X.; Müllen, K.; Haick, H.

Years: 2010

Published in: Adv. Mater., 22, 4317-4320

Cancer detection: The development of a cost-effective, portable and non-invasive diagnostic tool for detecting cancer from exhaled breath requires sensors that discriminate well between polar and nonpolar volatile organic compounds in highly humid atmospheres. Here we show that a chemiresistive bilayer comprised of a dense cap layer of discotic hexa-dodecyl-hexa-peri-hexabenzocoronene derivatives (hereby, HBC-C12) and a random network of carbon nanotubes (RN-CNT) as underlayer layer could fulfill these requirements.

Self-Assembly of Organic Monolayers as Protective and Conductive Bridges for Nanometric Surface – Mount Applications

Published: September 2010

Authors: Platzmann, I.; Haick, H.; Tannebaum, R.

Years: 2010

Published in: Acs Appl. Mater. Interf., 2( 9), 2585-2593

In this work, we present a novel surface-mount placement process that could potentially overcome the inadequacies of the currently used stencil-printing technology, when applied to devices in which either their lateral and/or their horizontal dimensions approach the nanometric scale. Our novel process is based on the “bottom-up” design of an adhesive layer, operative in the molecular/nanoscale level, through the use of self-assembled monolayers (SAMs) that could form protective and conductive bridges between pads and components. On the basis of previous results, 1,4-phenylene diisocyanide (PDI) and terephthalic acid (TPA) were chosen to serve as the best candidates for the achievement of this goal. The quality and stability of these SAMs on annealed Cu surfaces (Rrms=0.15-1.1 nm) were examined in detail. Measurements showed that the SAMs of TPA and PDI molecules formed on top of Cu substrates created thermally stable organic monolayers with high surface coverage (∼90%), in which the molecules were closely packed and well-ordered. Moreover, the molecules assumed a standing-up phase conformation, in which the molecules bonded to the Cu substrate through one terminal functional group, with the other terminal group residing away from the substrate. To examine the ability of these monolayers to serve as “molecular wires,” i.e., the capability to provide electrical conductivity, we developed a novel fabrication method of a parallel plate junction (PPJ) in order to create symmetric Cu-SAM-Cu electrical junctions. The current-bias measurements of these junctions indicated high tunneling efficiency. These achievements imply that the SAMs used in this study can serve as conductive molecular bridges that can potentially bind circuital pads/components.

Monolayer- Capped Cubic Platinum Nnoparticles for Sensing Nonpolar Analyst in Highly Humid Atmospheres

Published: July 2010

Authors: Dovgolevsky, E.; Konvalina, G.; Tisch, U.; Haick, H.

Years: 2010

Published in: J. Phys. Chem. C., 114, 14042-14049

We report on the feasibility of cubic Pt nanoparticles (NPs) capped with four representative organic ligands, viz. oleylamine (ODA), 11-mercaptoundecanol, 11-mercaptoundecanoic acid, and benzylmercaptan, for sensing gaseous nonpolar analytes in humid atmospheres. Chemiresistors based on cubic Pt NPs with nonpolar ligands show a very large increase in resistance upon exposure to nonpolar analyte vapors, combined with a low sensitivity to polar analyte vapors, especially to water. The sensing mechanism can be understood in terms of analyte-induced changes in the NP−NP core distance and changes in the permittivity of the medium between the NPs. The sensing capabilities of the Pt NP chemiresistors for nonpolar molecules in highly humid atmospheres are demonstrated by dosing an ODA-capped cubic Pt NP sensor with air mixtures containing low octane concentrations and high humidity levels that are typical for many applications. The simple construction, low cost, stability, fast response, and high sensitivity to nonpolar molecules, together with the low sensitivity to water vapor, are promising features for sensing applications in real confounding atmospheres.

Detection of Lung, Breast, Colorectal and Prostate Cancers from Exhaled Breath Using a Singel Array of Nanosensors

Published: July 2010

Authors: Peng, G.; Hakim, M.; Broza, Y. Y.; Billan, S.; Abdah- Brotnyak, R.; Kuten, A.; Tisch, U.; Haick, H.

Years: 2010

Published in: Br. J. Cancer, 103, 542 – 551

BACKGROUND:

Tumour growth is accompanied by gene and/or protein changes that may lead to peroxidation of the cell membrane species and, hence, to the emission of volatile organic compounds (VOCs). In this study, we investigated the ability of a nanosensor array to discriminate between breath VOCs that characterise healthy states and the most widespread cancer states in the developed world: lung, breast, colorectal, and prostate cancers.

METHODS:
Exhaled alveolar breath was collected from 177 volunteers aged 20-75 years (patients with lung, colon, breast, and prostate cancers and healthy controls). Breath from cancerous subjects was collected before any treatment. The healthy population was healthy according to subjective patient’s data. The breath of volunteers was examined by a tailor-made array of cross-reactive nanosensors based on organically functionalised gold nanoparticles and gas chromatography linked to the mass spectrometry technique (GC-MS).

RESULTS:
The results showed that the nanosensor array could differentiate between ‘healthy’ and ‘cancerous’ breath, and, furthermore, between the breath of patients having different cancer types. Moreover, the nanosensor array could distinguish between the breath patterns of different cancers in the same statistical analysis, irrespective of age, gender, lifestyle, and other confounding factors. The GC-MS results showed that each cancer could have a unique pattern of VOCs, when compared with healthy states, but not when compared with other cancer types.

CONCLUSIONS:
The reported results could lead to the development of an inexpensive, easy-to-use, portable, non-invasive tool that overcomes many of the deficiencies associated with the currently available diagnostic methods for cancer

Systematic Cross-Linking Changes within a Self-Assembled Monolayer in a Nanogap Junction: A Tool for Investigating the Intermolecular Electronic Coupling

Published: February 2010

Authors: Paska, Y.; Haick, H.

Years: 2010

Published in: J. Am. Chem. Soc., 132, 1774–1775

Here, we show that a controllable cross-linking within a self-assembled monolayer can be used as a tool for investigating the (lateral) intermolecular coupling between adjacent organic molecules. We draw this conclusion based on macroscopic electrical experiments with self-assembled hexyltrichlorosilane (HTS) having different degrees of Si-O-Si intermolecular bonds in a planar nanogap junction.

Tuning Electrical Properties of Si Nanowire Field Effect Transistors by Molecular Engineering

Published: December 2009

Authors: Bashouti, M. Y.; Tung, R. T.; Haick, H.

Years: 2009

Published in: Small, 5 (23), 2761-2769

Exposed facets of n-type silicon nanowires (Si NWs) fabricated by a top-down approach are successfully terminated with different organic functionalities, including 1,3-dioxan-2-ethyl, butyl, allyl, and propyl-alcohol, using a two-step chlorination/alkylation method. X-ray photoemission spectroscopy and spectroscopic ellipsometry establish the bonding and the coverage of these molecular layers. Field-effect transistors fabricated from these Si NWs displayed characteristics that depended critically on the type of molecular termination. Without molecules the source-drain conduction is unable to be turned off by negative gate voltages as large as -20 V. Upon adsorption of organic molecules there is an observed increase in the “on” current at large positive gate voltages and also a reduction, by several orders of magnitude, of the “off” current at large negative gate voltages. The zero-gate voltage transconductance of molecule-terminated Si NW correlates with the type of organic molecule. Adsorption of butyl and 1,3-dioxan-2-ethyl molecules improves the channel conductance over that of the original SiO(2)-Si NW, while adsorption of molecules with propyl-alcohol leads to a reduction. It is shown that a simple assumption based on the possible creation of surface states alongside the attachment of molecules may lead to a qualitative explanation of these electrical characteristics. The possibility and potential implications of modifying semiconductor devices by tuning the distribution of surface states via the functionality of attached molecules are discussed.

Sniffing the Unique ”Odor Print” of Non-Small-Cell Lung Cancer with Gold Nanoparticles

Published: November 2009

Authors: Barash, O.; Peled, N.; Hirsch, F. R.; Haick, H.

Years: 2009

Published in: Small, 5 (22), 2618-2624

A highly sensitive and fast-response array of sensors based on gold nanoparticles, in combination with pattern recognition methods, can distinguish between the odor prints of non-small-cell lung cancer and negative controls with 100% accuracy, with no need for preconcentration techniques. Additionally, preliminary results indicate that the same array of sensors might serve as a better tool for understanding the biochemical source of volatile organic compounds that might occur in cancer cells and appear in the exhaled breath, as compared to traditional spectrometry techniques. The reported results provide a launching pad to initiate a bedside tool that might be able to screen for early stages of lung cancer and allow higher cure rates. In addition, such a tool might be used for the immediate diagnosis of fresh (frozen) tissues of lung cancer in operating rooms, where a dichotomic diagnosis is crucial to guide surgeons.

Diagnosing Lung Cancer in Exhaled Breath Using Au Nanoparticles

Published: August 2009

Authors: Peng, G.; Tisch, U.; Adams, O.; Hakim, M.; Shehada, N.; Broza, Y. Y.; Billan, S.; Abdah- Brotnyak, R.; Kuten, A.; Haick, H.

Years: 2009

Published in: Nat. Nanotechnol., 4, 669-673

Conventional diagnostic methods for lung cancer are unsuitable for widespread screening because they are expensive and occasionally miss tumours. Gas chromatography/mass spectrometry studies have shown that several volatile organic compounds, which normally appear at levels of 1–20 ppb in healthy human breath, are elevated to levels between 10 and 100 ppb in lung cancer patients. Here we show that an array of sensors based on gold nanoparticles can rapidly distinguish the breath of lung cancer patients from the breath of healthy individuals in an atmosphere of high humidity. In combination with solid-phase microextraction, gas chromatography/mass spectrometry was used to identify 42 volatile organic compounds that represent lung cancer biomarkers. Four of these were used to train and optimize the sensors, demonstrating good agreement between patient and simulated breath samples. Our results show that sensors based on gold nanoparticles could form the basis of an inexpensive and non-invasive diagnostic tool for lung cancer.

Molecular Electronics at Metal/Semiconductor Junctions. Si Inversion by Sub-Nanometer Molecular Films

Published: May 2009

Authors: Yaffe, O.; Scheres, L.; Puniredd, S. R.; Stein, N.; Biller, A.; Har-Lavan, R.; Shpaisman, H.; Zuilhof, H.; Haick, H.; Cahen, D.; Vilan, A.

Years: 2009

Published in: Nano Lett., 9 (6), 2390–2394

Electronic transport across n-Si-alkyl monolayer/Hg junctions is, at reverse and low forward bias, independent of alkyl chain length from 18 down to 1 or 2 carbons! This and further recent results indicate that electron transport is minority, rather than majority carrier dominated, occurs via generation and recombination, rather than (the earlier assumed) thermionic emission, and, as such, is rather insensitive to interface properties. The (m)ethyl results show that binding organic molecules directly to semiconductors provides semiconductor/metal interface control options, not accessible otherwise.

Detection of Nonpolar Molecules by Means of Carrier Scattering in Random Networks of Carbon Nanotubes: Towards Diagnosis of Diseases via Breath Samples

Published: April 2009

Authors: Peng, G.; Tisch, U.; Haick, H.

Years: 2009

Published in: Nano Lett., 9 (4), 1362-1368

Field effect transistors (FETs) based on random networks (RNs) of single-wall carbon nanotubes (CNTs) have several technological advantages. However, the low sensitivity (or no sensitivity) of RN-CNT sensors to nonpolar molecules is a problematic, negative feature that limits their applications in the detection of a wide variety of diseases via breath samples. In this paper, we show experimental evidence for the detection of both individual nonpolar molecules and patterns of nonpolar molecules, even in the presence of polar molecules in the same environment. We do so by preparing RN-CNT FETs and functionalizing them with organic films that exhibit distinctive electrical and physical (or mechanical) characteristics. Exposing the functionalized RN-CNTs to representative nonpolar breath biomarkers, and, for comparison, to polar molecules in the gas phase, and monitoring the changes in conductance, work function, and organic film thickness show sensitivity toward nonpolar molecules. We explain this observation by carrier scattering as a result of swelling of the organic film upon exposure to (nonpolar) chemical agents. Hence, the sensitivity towards nonpolar molecules can be tailored, even in the presence of polar molecules, by controlling the scattering of charge carrier through deliberate functionalization of CNTs. As examples for the technological impact of our findings, we describe ways to detect lung cancer and kidney disease using specially designed RN-CNT sensor arrays.

Sponge-like Structures of Hexa-peri-hexabenzocoronenes Derivatives Enhances the Sensitivity of Chemiresistive Carbon Nanotubes to Nonpolar Volatile Organic Compounds

Published: April 2009

Authors: Zilberman, Y.; Tisch, U.; Pisula, W.; Feng, X.; Müllen, K.; Haick, H.

Years: 2009

Published in: Langmuir, 25 (9), 5411–5416

Cancer is a leading health hazard, and lung cancer is its most common form. Breath testing is a fast, noninvasive diagnostic method which links specific volatile organic compounds (VOCs) in exhaled breath to medical conditions. Arrays of sensors based on carbon nanotubes (CNTs) could in principle detect cancer by differentiating between the VOCs found in the breath of healthy and sick persons, but the notoriously low sensitivity of CNT sensors to nonpolar VOCs limits their accuracy. In this study, we have achieved a marked improvement of the sensitivity and selectivity of random networks (RNs) of CNT chemiresistors to nonpolar VOCs by functionalizing them with self-assembled, spongelike structures of discotic hexa-peri-hexabenzocoronene (HBC) derivatives. We observed swelling of the organic film by monitoring the changes of organic film thickness during exposure and propose that the expansion of the spongelike organic overlayer creates scattering centers in the underlying RN-CNTs by physically distancing the CNTs at their intersections. The results presented here could lead to the development of robust sensors for nonpolar VOCs of cancer breath, which have hitherto been difficult to trace.

Silicon Nanowires Terminated with Methyl Functionalities Exhibit Stronger Si-C bonds than Equivalent 2D Surfaces

Published: March 2009

Authors: Bashouti, M. Y.; Paska, Y.; Puniredd, S. R.; Stelzner, T.; Christiansen, S.; Haick, H.

Years: 2009

Published in: Phys. Chem. Chem. Phys., 11, 3845–3848

Silicon nanowires (Si NWs) terminated with methyl functionalities exhibit higher oxidation resistance under ambient conditions than equivalent 2D Si(100) and 2D Si(111) surfaces having similar or 10–20% higher initial coverage. The kinetics of methyl adsorption as well as complementary surface analysis by XPS and ToF SIMS attribute this difference to the formation of stronger Si–C bonds on Si NWs, as compared to 2D Si surfaces. This finding offers the possibility of functionalising Si NWs with minimum effect on the conductance of the near-gap channels leading towards more efficient Si NW electronic devices.

Chemically Sensitive Resistors Based on Monolayer-Capped Cubic Nanoparticles: Towards Configurable Nanoporous Sensors

Published: March 2009

Authors: Dovgolevsky, E.; Tisch, U.; Haick, H.

Years: 2009

Published in: Small, 5 (10), 1158-1161

Cube roots: Chemiresistors based on cubic monolayer-capped nanoparticles (MCNPs) produce a higher electrical response upon exposure to volatile organic compounds than those based on spherical MCNPs. These observations are explained in terms of the higher swellability of cubic MCNPs compared to spherical MCNPs

Controlling Surface Energetics of Silicon by Intermolecular Interactions between Parallel Self-Assembled Molecular Dipoles

Published: January 2009

Authors: Paska, Y.; Haick, H.

Years: 2009

Published in: J. Phys. Chem. C., 113 (5), 1993-1997

We show that the electrical properties of Si surfaces can be controlled systematically by the extent of intermolecular interactions between molecular dipoles that self-assemble in parallel on the Si surfaces. We draw this conclusion on the basis of experiments with self-assembled hexyltrichlorosilane molecules on SiOx/Si surfaces, with different degrees of Si−O−Si intermolecular bonds. Our results indicate that systematic control of intermolecular interactions of organic molecules on a semiconductor surface provides an important additional molecular handle, in addition to varying the individual molecule’s dipole, for controlling the surface energetics of semiconductor surfaces and, by extension, of semiconductor- and metal-containing interfaces, thus significantly enhancing the molecular control of electronic surfaces and interfaces.

Direct Observation of the Transition Point between Quasi-Spherical and Cubic Nanoparticles in Two-Step Seed-Mediated Growth Method

Published: October 2008

Authors: Dovgolevsky, E.; Haick, H.

Years: 2008

Published in: Small, 4 (11), 2059-2066

An aqueous seed-mediated growth method is adapted to explore the shape transformation of quasi-spherical Au seeds to nanocubes in a direct and continuous manner. Quenching the growth process at varied reaction-duration times and exploring the intermediate products by high-resolution transmission electron microscopy and UV/vis spectroscopy shows an abrupt cuboctahedral-to-nanocube transition at 25-27 nm without any change in the nanoparticle size. The size of the obtained nanocubes remains constant (25-27 nm) until most (>90%) of the cuboctahedral nanoparticles are transformed to nanocubes. At this point, the (25-27 nm) nanocubes initiate further continuous and homogeneous growth until they reach 50-nm Au cubes. These observations are ascribed to a scenario in which the kinetically controlled growth mode of the nanoparticle is significantly affected by the surface self-diffusion of metal adatoms, especially when the adatom’s self-diffusion distance is comparable with the nanoparticle’s size.

Detecting Simulated Patterns of Lung Cancer Biomarkers by Random Network of Single-Walled Carbon Nanotubes Coated with Nonpolymeric Organic Materials, Nano Lett.

Published: October 2008

Authors: Peng, G.; Trock, E.; Haick, H.

Years: 2008

Published in: Nano Lett., 8 (11), 3631–3635

An array of chemiresistive random network of single-walled carbon nanotubes coated with nonpolymeric organic materials shows a high potential for diagnosis of lung cancer via breath samples. The sensors array shows excellent discrimination between the volatile organic compounds (VOCs) found in the breath of patients with lung cancer, relative to healthy controls, especially if the sensors array is preceded with either water extractor and/or preconcentrator of VOCs. The pattern compositions of the healthy and cancerous states were determined by gas-chromatography linked with mass-spectroscopy (GC-MS) analysis of real exhaled breath.

Highly Stable Organic Monolayers for Reacting Si with Further Functionalities: The Effect of C-C Bond nearby the Si Surface

Published: September 2008

Authors: Puniredd, S. R.; Assad, O.; Haick, H.

Years: 2008

Published in: J. Am. Chem. Soc., 130 (41), 13727-13734

Crystalline Si(111) surfaces have been alkylated in a two-step chlorination/alkylation process using various organic molecules having similar backbones but differing in their C-C bond closest to the silicon surface (i.e., C-C vs C=C vs C[triple bond]C bonds). X-ray photoelectron spectroscopic (XPS) data show that functionalization of silicon surfaces with propenyl magnesium bromide (CH3-CH=CH-MgBr) organic molecules gives nearly full coverage of the silicon atop sites, as on methyl- and propynyl-terminated silicon surfaces. Propenyl-terminated silicon surface shows less surface oxidation and is more robust against solvent attacks when compared to methyl- and propynyl-terminated silicon surfaces. We also show a secondary functionalization process of propenyl-terminated silicon surface with 4′-[3-Trifluoromethyl-3H-diazirin-3-yl]-benzoic acid N-hydroxysuccinimide ester [TDBA-OSu] cross-linker. The Si-CH=CH-CH3 surfaces thus offer a means of attaching a variety of chemical moieties to a silicon surface through a short linking group, enabling applications in molecular electronics, energy conversion, catalysis, and sensing.

Coverage Effect of Self-Assembled Polar Molecules on the Surface Energetics of Silicon

Published: July 2008

Authors: Gozlan, N.; Haick, H.

Years: 2008

Published in: J. Phys. Chem. C., 112 (33), 12599-12601

We show here that optimal control over the work function of Si can be achieved even with half coverage of molecular dipoles, especially when the pinholes present on the surface are smaller than the depletion region of the semiconductor. Higher coverage than an optimal value contributes minor (or, no) further changes in the work function of the same semiconductor. The results imply that the requirements on the molecules used to control the electrical properties of Si are significantly and nearly completely relaxed. Therefore, the ability of the molecules to form pinhole-free coverage will not be important after a specific coverage.

Tailoring the Work Function of Gold Surface by Controlling Coverage and Disorder of Polar Molecular Monolayers

Published: July 2008

Authors: Gozlan, N.; Tisch, U.; Haick, H.

Years: 2008

Published in: J. Phys. Chem. C., 112 (33), 12988-12992

We show here that the work function of Au can be controlled not only by the magnitude and direction of adsorbed polar molecules but also by the molecular coverage and (dis)order within the molecular patterns. Molecular monolayers composed of two types of molecules with opposite dipoles were deposited on Au films containing the changes of the work function due to variation of molecular coverage and disorder were monitored. The results indicate that the requirements on molecular layers covering Au surfaces are significantly relaxed and that partial, disordered monolayers can be used to tailor the work function of metal surfaces.

Highly Stable Organic Modification of Si (111) Surfaces: Towards Reacting Si with Further Functionalities while Preserving the Desirable Chemical Properties of Full Si-C atop Site Terminations

Published: July 2008

Authors: Puniredd, S. R.; Assad, O.; Haick, H.

Years: 2008

Published in: J. Am. Chem. Soc., 130 (29), 9184-9185

Si(111) surfaces modified by covalent Si-CH=CH-CH3 functionality, with no intervening oxide, show coverage of all atop Si sites and superior chemical stability in ambient conditions and water, as compared with molecules that form nearly full coverage (e.g., Si-C C-CH3 and Si-CH3 surfaces).

Making Contact: Connecting Molecules Electrically to the Macroscopic World

Published: June 2008

Authors: Haick, H.; Cahen, D.

Years: 2008

Published in: Prog. Surf. Sci., 83 (4), 217-261

Introducing organic molecules in electronics, in general, and as active electronic transport components, in particular, is to no small degree limited by the ability to connect them electrically to the outside world. Making useful electrical contacts to them requires achieving this either without altering the molecules, or if they are affected, then in a controlled fashion. This is not a trivial task because most known methods to make such contacts are likely to damage the molecules. In this progress report we review many of the various ways that have been devised to make electrical contacts to molecules with minimal or no damage. These approaches include depositing the electronic conducting contact material directly on the molecules, relying on physical interactions, requiring chemical bond formation between molecule and electrode materials, “ready-made” contacts (i.e., contact structures that are prepared in advance), and contacts that are prepared insitu. Advantages and disadvantages of each approach, as well as the possibilities that they can be used practically, are discussed in terms of molecular reactivity, surface and interfacial science.

Contacting Organic Molecules by means of Soft Methods: Towards Molecule-Based Electronic Devices

Published: March 2008

Authors: Haick, H.; Cahen, D.

Years: 2008

Published in: Acc. Chem. Res., 41 (3), 359-366

Can we put organic molecules to use as electronic components? The answer to this question is to no small degree limited by the ability to contact them electrically without damaging the molecules. In this Account, we present some of the methods for contacting molecules that do not or minimally damage them and that allow formation of electronic junctions that can become compatible with electronics from the submicrometer to the macroscale. In “Linnaean” fashion, we have grouped contacting methods according to the following main criteria: (a) is a chemical bond is required between contact and molecule, and (b) is the contact “ready-made”, that is, preformed, or prepared in situ? Contacting methods that, so far, seem to require a chemical bond include spin-coating a conductive polymer and transfer printing. In the latter, a metallic pattern on an elastomeric polymer is mechanically transferred to molecules with an exposed terminal group that can react chemically with the metal. These methods allow one to define structures from several tens of nanometers size upwards and to fabricate devices on flexible substrates, which is very difficult by conventional techniques. However, the requirement for bifunctionality severely restricts the type of molecules that can be used and can complicate their self-assembly into monolayers. Methods that rely on prior formation of the contact pad are represented by two approaches: (a) use of a liquid metal as electrode (e.g., Hg, Ga, various alloys), where molecules can be adsorbed on the liquid metal and the molecularly modified drop is brought into contact with the second electrode, the molecules can be adsorbed on the second electrode and then the liquid metal brought into contact with them, or bilayers are used, with a layer on both the metal and the second electrode and (b) use of preformed metal pads from a solid substrate and subsequent pad deposition on the molecules with the help of a liquid. These methods allow formation of contacts easily and rapidly and allow many types of monolayers and metals to be analyzed. However, in their present forms such approaches are not technologically practical. Direct in situ vacuum evaporation of metals has been used successfully only with bifunctional molecules because it is too invasive and damaging, in general. A more general approach is indirect vacuum evaporation, where the metal atoms and clusters, emitted from the source, reach the sample surface in an indirect line of sight, while cooled by multiple collisions with an inert gas. This method has clear technological possibilities, but more research is needed to increase deposition efficiency and find ways to characterize the molecules at the interface and to prevent metal penetration between molecules or through pinholes, also if molecules lack reactive termination groups. This Account stresses the advantages, weak points, and possible routes for the development of contacting methods. This way it shows that there is at present no one ideal soft contacting method, whether it is because of limitations and problems inherent in each of the methods or because of insufficient understanding of the interfacial chemistry and physics. Hopefully, this Account will present the latter issue as a research challenge to its readers.

Oxidation of Polycrystalline Copper Thin Films at Ambient Conditions

Published: January 2008

Authors: Platzmann, I.; Brener, R.; Haick, H.; Tannebaum, R.

Years: 2008

Published in: J. Phys. Chem. C., 112 (4), 1101-1108

Qualitative and quantitative studies of the oxidation of polycrystalline copper (Cu) thin films upon exposure to ambient air conditions for long periods (on the order of several months) are reported in this work. Thin films of Cu, prepared by thermal evaporation, were analyzed by means of X-ray photoelectron spectroscopy (XPS) to gain an understanding on the growth mechanism of the surface oxide layer. Analysis of high-resolution Cu LMM, Cu2p3/2, and O1s spectra was used to follow the time dependence of individual oxide overlayer thicknesses as well as the overall oxide composite thickness. Transmission electron microscopy (TEM) and spectroscopic ellipsometry (SE) were used to confirm the results obtained from XPS measurements. Three main stages of copper oxide growth were observed:  (a) the formation of a Cu2O layer, most likely due to Cu metal ionic transport toward the oxide−oxygen interface, (b) the formation of a Cu(OH)2 metastable overlayer, due to the interactions of Cu ions with hydroxyl groups present at the surface, and (c) the transformation of the Cu(OH)2 metastable phase to a more stable CuO layer. These three stages were found to occur simultaneously and to be mutually dependent on each other. The findings of this study may provide guidance in choosing the optimal conditions to fabricate and store copper-based ultra-large-scale integrated (ULSI) circuits.

Electrostatic Properties of Ideal and Non-Idea Polar Organic Monolayers: Implications for Electronic Devices

Published: November 2007

Authors: Natan, A.; Kronik, L.; Haick, H.; Tung, R. T.

Years: 2007

Published in: Adv. Mater., 19, 4103-4117

Molecules in (or as) electronic devices are attractive because the variety and flexibility inherent in organic chemistry can be harnessed towards a systematic design of electrical properties. Specifically, monolayers of polar molecules introduce a net dipole, which controls surface and interface barriers and enables chemical sensing via dipole modification. Due to the long range of electrostatic phenomena, polar monolayer properties are determined not only by the type of molecules and/or bonding configuration to the substrate, but also by size, (dis-)order, and adsorption patterns within the monolayer. Thus, a comprehensive understanding of polar monolayer characteristics and their influence on electronic devices requires an approach that transcends typical chemical designs, i.e., one that incorporates long-range effects, in addition to short-range effects due to local chemistry. We review and explain the main uses of polar organic monolayers in shaping electronic device properties, with an emphasis on long-range cooperative effects and on the differences between electrical properties of uniform and non-uniform monolayers.

Chemical Sensors Based Molecularly Modified Metallic Nanoparticles

Published: November 2007

Authors: Haick, H.

Years: 2007

Published in: J. Phys. D, 40, 7173-7186

 This paper presents a concise, although admittedly non-exhaustive, didactic review of some of the main concepts and approaches related to the use of molecularly modified metal nanoparticles in or as chemical sensors. This paper attempts to pull together different views and terminologies used in sensors based on molecularly modified metal nanoparticles, including those established upon electrochemical, optical, surface Plasmon resonance, piezoelectric and electrical transduction approaches. Finally, this paper discusses briefly the main advantages and disadvantages of each of the presented class of sensors.

Controlling Au/n-GaAs Junctions by Partial Molecular Monolayers

Published: November 2006

Authors: Haick, H.; Pelz, J. P.; Ligonzo, T.; Ambrico, M.; Cahen, D.; Cai, W.; Marginean, C.; Tivarus, C.; Tung, R. T.

Years: 2006

Published in: Phys. Status Solidi A, 203 (14), 3438-3451

A dipole-layer approach is adapted to describe the electrostatic potential and electronic transport through metal/semiconductor junctions with a discontinuous monolayer of polar molecules at the metal/semiconductor interface. The effective barrier height of those junctions, which have small pinholes, embedded in a molecular layer, which introduces a negative {positive} dipole (i.e., a dipole whose negative {positive} pole is the one that is closest to the semiconductor surface) on an n-type {p-type} semiconductor, is often “tunable” by the magnitude and density of the dipoles. If the lateral dimensions of a molecule-free pinhole at the interface exceed the semiconductor depletion width, carrier transport is not influenced by the molecular layer and the “effective” barrier height is the nominal metal/semiconductor barrier height. If the molecular layer introduces a positive {negative} dipole on an n-type {p-type} semiconductor, enhanced field emission at edges of small pinholes might lead to a leakage- and/or an edge-current component resulting in an effective barrier height lower than the nominal one. We support these conclusions by direct measurements of the nm-scale electronic behaviour of a Au/n-GaAs diode with a discontinuous monolayer of dicarboxylic acids at the interface, using Ballistic Electron Emission Microscopy

Probing Electrical Properties of Molecule-Controlled, and Plasma Nitrided GaAs Surface: Different Approaches for Modifying Electrical Characteristics of Metal/GaAs Diodes

Published: August 2006

Authors: Ambrico, M.; Losurdo, M.; Capezzuto, P.; Bruno, G.; Ligonzo, T.; Haick, H.

Years: 2006

Published in: Appl. Surf. Sci., 252 (21), 7636-7641

This work shows how partial monolayer of organic molecules or radio-frequency remote plasma surface treatment affects the electrical transport across Au/n-GaAs junctions. In the first case, a series of molecules with systematically varying dipole moment were adsorbed on n-GaAs surfaces, whereas in the second case GaN ultra-thin layers with different thickness were formed by N2–H2 GaAs plasma nitridation, prior to contact deposition. The characteristics of electrical charge transport across the resulting interfaces were studied by current–voltage (I–V), internal photoemission (IPE), and capacitance–voltage (C–V) techniques. In this way, we find that the simplest description for the experimentally observed data is in terms of two different barrier heights, rather than one barrier height, at the interface. The first could be identified with areas free of modified GaAs, and the second with areas controlled by electrostatic effects of adjacent dipolar domains, which affects also semiconductor regions under the film’s pinholes.

Electrical Characteristics and Chemical Stability of Non-Oxidized, Methyl-Terminated Silicon Nanowires

Published: June 2006

Authors: Haick, H.; Hurley, P. T.; Hochbaum, A. I.; Yang, P.; Lewis, N. S.

Years: 2006

Published in: J. Am. Chem. Soc., 128 (28), 8990-8991

Silicon nanowires (Si NWs) modified by covalent Si−CH3 functionality, with no intervening oxide, show atmospheric stability, high conductance values, low surface defect levels, and allow for the formation of air-stable Si NW Field-Effect Transistors (FETs) having on−off ratios in excess of 105 over a relatively small gate voltage swing (±2 V).

Controlling Semiconductor/Metal Junction Barriers by Incomplete, Nonideal Molecular Monolayers

Published: May 2006

Authors: Haick, H.; Ambrico, M.; Ligonzo, T.; Tung, R. T.; Cahen, D.

Years: 2006

Published in: J. Am. Chem. Soc., 128 (21), 6854-6869

We study how partial monolayers of molecular dipoles at semiconductor/metal interfaces can affect electrical transport across these interfaces, using a series of molecules with systematically varying dipole moment, adsorbed on n-GaAs, prior to Au or Pd metal contact deposition, by indirect evaporation or as “ready-made” pads. From analyses of the molecularly modified surfaces, we find that molecular coverage is poorer on low- than on high-doped n-GaAs. Electrical charge transport across the resulting interfaces was studied by current-voltage-temperature, internal photoemission, and capacitance-voltage measurements. The data were analyzed and compared with numerical simulations of interfaces that present inhomogeneous barriers for electron transport across them. For high-doped GaAs, we confirm that only the former, molecular dipole-dependent barrier is found. Although no clear molecular effects appear to exist with low-doped n-GaAs, those data are well explained by two coexisting barriers for electron transport, one with clear systematic dependence on molecular dipole (molecule-controlled regions) and a constant one (molecule-free regions, pinholes). This explains why directly observable molecular control over the barrier height is found with high-doped GaAs: there, the monolayer pinholes are small enough for their electronic effect not to be felt (they are “pinched off”). We conclude that molecules can control and tailor electronic devices need not form high-quality monolayers, bind chemically to both electrodes, or form multilayers to achieve complete surface coverage. Furthermore, the problem of stability during electron transport is significantly alleviated with molecular control via partial molecule coverage, as most current flows now between, rather than via, the molecules.

Effect of Molecular Binding to Semiconductor on a Metal/ Molecule/Semiconductor Junction Behavior

Published: May 2005

Authors: Haick, H.; Ghabboun, J.; Niitsoo, O.; Cohen, H.; Cahen, D.; Vilan, A.; Hwang, J.; Wan, A.; Amy, F.; Kahn, A.

Years: 2005

Published in: J. Phys. Chem. B., 109, 9622-9630

Diodes made by (indirectly) evaporating Au on a monolayer of molecules that are adsorbed chemically onto GaAs, via either disulfide or dicarboxylate groups, show roughly linear but opposite dependence of their effective barrier height on the dipole moment of the molecules. We explain this by Au-molecule (electrical) interactions not only with the exposed end groups of the molecule but also with its binding groups. We arrive at this conclusion by characterizing the interface by in situ UPS-XPS, ex situ XPS, TOF-SIMS, and Kelvin probe measurements, by scanning microscopy of the surfaces, and by current-voltage measurements of the devices. While there is a very limited interaction of Au with the dicarboxylic binding groups, there is a much stronger interaction with the disulfide groups. We suggest that these very different interactions lead to different (growth) morphologies of the evaporated gold layer, resulting in opposite effects of the molecular dipole on the junction barrier height.

Pd versus Au as Evaporated Metal Contacts to Molecules

Published: January 2005

Authors: Haick, H.; Ghabboun, J.; Cahen, D.

Years: 2005

Published in: Appl. Phys. Lett., 86 (4), 042113/1-042113/3

Indirect e-beam evaporation of metal on a cooled substrate that allows making reproducible and gentle electrical contact to molecular films of organic molecules yields strikingly different results with Pd and Au. This is attributed to different growth modes of the metals, which lead to different molecule/metal interactions and to Au penetration in between the molecules. These differences can radically change the effect of the molecules on the resulting junctions.

Discontinuous Molecular Films Can Control Metal/Semiconductor Junctions

Published: December 2004

Authors: Haick, H.; Ambrico, M.; Ligonzo, T.; Cahen, D.

Years: 2004

Published in: Adv. Mater., 16 (23-24), 2145-2151

Molecular control over charge transport across a metal/semiconductor interface persists even if there is only a partial monolayer of polar molecules at the interface. This is because the long-range electrostatic effect of the dipole layer also affects the semiconductor regions under the film’s pinholes. Thus, all types of polar molecules that show average order at the interface can be used.

Contacting Organic Molecules by Metal Evaporation

Published: August 2004

Authors: Haick, H.; Ambrico, M.; Ghabboun, J.; Ligonzo, T.; Cahen, D.

Years: 2004

Published in: Phys. Chem. Chem. Phys., 6, 4538-4541

Reproducible electrical contacts to organic molecules are created non-destructively by indirectelectron beam evaporation of Pd onto molecular films on cooled substrates. In contrast, directlyevaporated contacts damage the molecules seriously. Our conclusions are based on correlating trends in properties of a series of molecules with systematically varying, exposed functional groups, with trends in the electrical behaviour of Pd/molecule/GaAs junctions, where these same molecules are part of the junctions.

Controlled Mass Transport as a Means for Obtaining Selective Photocatalysis

Published: August 2003

Authors: Ghosh, M. S.; Haick, H.; Paz, Y.

Years: 2003

Published in: J. Photochem. Photobiol. A: Chem., 160 (1-2), 77-85

The photoinduced degradation of pollutants in water and air using titanium dioxide attracts an increasing attention. Unfortunately, titanium dioxide has very poor selectivity and cannot differentiate between highly hazardous contaminants that are often non-biodegradable and contaminants of low toxicity that are often very easy to handle biologically. A new approach for enhancing the photocatalytic degradation of specific contaminants in air or water is presented herein. The method is based upon selective physisorption of the contaminants on molecular recognition sites located in the vicinity of titanium dioxide micro-domains, followed by surface-diffusion of the contaminants to the photocatalytic sites. The feasibility of this approach is demonstrated using β-cyclodextrin as the host and 2-methyl-1,4-naphthoquinone and the dye-stuff Chicago Blue as guests. A degradation rate increase of 200 and 70% relative to samples that did not contain the molecular recognition sites was found for the former contaminant and for the latter contaminant, respectively. This was achieved without any significant damage to the organic molecular recognition sites, thus encouraging attempts to materialize this approach on a practical level.

“Dark” Photocatalysis: The Degradation of Organic Molecules Anchored to Dark Microdomains of Titanium Dioxide

Published: June 2003

Authors: Haick, H.; Paz, Y.

Years: 2003

Published in: ChemPhysChem, 4 (6), 617-620

Join the dark side: Titanium dioxide is widely used as a photocatalyst for the degradation of many contaminants in air, in water and on solid surfaces. By anchoring self-assembled monolayers onto “dark” microdomains of titanium dioxide (see picture) and measuring their photodegradation kinetics, it is shown that molecules located on dark areas at the vicinity of illuminated domains of titanium dioxide might be prone to an oxidizing attack by oxidizing species that out-diffuse from the illuminated areas.

Effect of Metallic Microdomains on the Chemisorption of Octadecyltrichlorosilane onto Titanium Dioxide

Published: March 2003

Authors: Haick, H.; Segatelian, Y.; Paz, Y.

Years: 2003

Published in: Langmuir, 19, 2540-2544

The formation of octadecyltrichlorosilane monolayers on titanium dioxide was studied in structures consisting of microdomains of TiO2 and noble metals such as gold and platinum. On the basis of Fourier transform infrared and Auger electron spectroscopies, it was found that the density of the monolayers on the TiO2 surface was significantly higher in these structures than in plain samples that did not contain the metallic microdomains. This effect, whose range was unexpectedly long (up to 80 microns), was found to depend on the stripes’ width and upon the ratio between the width of the metallic domains and that of the titanium dioxide domains. Applying a positive potential bias to the titanium dioxide during the chemisorption of the monolayer had a similar effect.

Long Range Effect of Noble Metals on the Photocatalytic Properties of Titanium Dioxide

Published: February 2003

Authors: Haick, H.; Paz, Y.

Years: 2003

Published in: J. Phys. Chem. B., 107 (10), 2319–2326

Well-defined structures comprised of alternating microstripes of noble metals (Au, Pt) and TiO2, covered with self-assembled monolayers (SAMs), are used to study long-range metallic effects on the photodegradation of the monolayers. It was found that under certain conditions, the presence of a metal in the vicinity of the photocatalyst does not increase its photoefficiency but, in fact, might reduce it significantly, in comparison with a bare photocatalyst. This effect depends on the size of the domains, as well as on humidity and the type of metal. It is suggested that although metal-induced charge separation is beneficial in promoting the production of hydroxyl radicals needed for the first steps of the degradation process, charge separation might also become detrimental under conditions that decrease the back-diffusion of reduced species, such as hydroperoxy radicals, needed at later stages of the degradation process.

Photocatalytic Degradation of Self-Assembled Monolayers Anchored at the Vicinity of Titanium Dioxide

Published: January 2002

Authors: Zemel, E.; Haick, H.; Paz, Y.

Years: 2002

Published in: J. Adv. Oxid. Technol., 5 (1), 27-32

In order to study the photodegradation of molecules located at the vicinity of a titanium dioxide photocatalyst, a well-defined structure comprised of alternating micro-stripes of TiO2 and silicon was prepared on silicon wafers. Onto this structure, a cross-linked self-assembled monolayer (SAM) of Octadecyltrichlorosilane (OTS) was chemisorbed. The kinetics of the photodegradation of the anchored SAM on the hybrid structure was then measured in-situ by FTIR under controlled humidity (8% RH). It was found that the photogenerated oxidizing species, formed on the titanium dioxide well-defined micro-domains, are capable of inducing, within minutes, the mineralization of the aliphatic chains anchored to the inert silicon domains, even when these chains were located as far as 20 microns away from the titanium dioxide micro-zones. Based on complementary experiments with alkanethiols on gold in a Au/TiO2 hybrid system, it was shown that the observed remote mineralization was not based on a diffusion – through – air mechanism. The observation that the oxidizing species can induce mineralization far from the locus of their formation may have large effect on the design and modeling of porous photocatalysts having “dark” pores.

Selective Photocatalysis by Means of Molecular Recognition

Published: January 2001

Authors: Ghosh, M. S.; Haick, H.; Schvartzman, M.; Paz, Y.

Years: 2001

Published in: J. Am. Chem. Soc., 123 (43), 10776-10777

Remote Photocatalytic Activity as Probed by Measuring the Degradation of Self-Assembled Monolayers Anchored Near Micro-Domains of Titanium Dioxide

Published: January 2001

Authors: Haick, H.; Paz, Y.

Years: 2001

Published in: J. Phys. Chem. B., 105, 3045-3051

A cross-linked self-assembled monolayer (SAM) of octadecyltrichlorosilane (OTS) was chemisorbed on well-defined structures, comprised of alternating microstripes of TiO2 and silicon. The kinetics of the photodegradation of the anchored SAM on the hybrid structure was then measured in situ by FTIR under controlled humidity and surface temperature. It was found that mineralization of the aliphatic chains anchored to the inert silicon domains can occur, even when these chains are located as far as 20 μm away from the photocatalytic titanium dioxide microdomains. An apparent first-order kinetics was found for each of the two domain types. Apparent activation energies were calculated on the basis of the temperature-dependent measurements. The observation that the oxidizing species can induce mineralization far from the locus of their formation may have large effect on the design and modeling of porous photocatalysts having “dark” pores and on the developing of hybrid photocatalysts.

Sniffing Chronic Renal Failure in Rat Models via an Array of Random Network of Single-Walled Carbon Nanotubes

Authors: Haick, H.; Hakim, M.; Patrascua, M.; Levenberg, C.; Shehada, N.; Nakhoul, F.; Abassi, Z.

Years: 2009

Published in: ACS Nano., 3 (5), 1258-1266

In this study, we use an experimental model of bilateral nephrectomy in rats to identify an advanced, yet simple nanoscale-based approach to discriminate between exhaled breath of healthy states and of chronic renal failure (CRF) states. Gas chromatography/mass spectroscopy (GC-MS) in conjugation with solid-phase microextraction (SPME) of healthy and CRF breath, collected directly from the trachea of the rats, identified 15 common volatile organic compounds (VOCs) in all samples of healthy and CRF states and 27 VOCs that appear in CRF but not in healthy states. Online breath analysis via an array of chemiresistive random network of single-walled carbon nanotubes (SWCNTs) coated with organic materials showed excellent discrimination between the various breath states. Stepwise discriminate analysis showed that enhanced discrimination capacity could be achieved by decreasing the humidity prior to their analysis with the sensors’ array. Furthermore, the analysis showed the adequacy of using representative simulated VOCs to imitate the breath of healthy and CRF states and, therefore, to train the sensors’ array the pertinent breath signatures. The excellent discrimination between the various breath states obtained in this study provides expectations for future capabilities for diagnosis, detection, and screening various stages of kidney disease, especially in the early stages of the disease, where it is possible to control blood pressure and protein intake to slow the progression.

Controlling Properties of Field Effect Transistors by Intermolecular Cross-linking of Molecular Dipoles

Authors: Paska, Y.; Haick, H.

Years: 2009

Published in: Appl. Phys. Lett., 95, 233103/1-233103/3

In this study, we show that systematic molecular control over a silicon-on-insulator field effect transistor (SOI-FET) device can be achieved by controlling the Si–O–Si intermolecular interactions between adjacent trichlorosilane molecules. This is attributed to the fact that Si–O–Si intermolecular bonds between the parallel molecular dipoles change the overall charge distribution within the organic layer, and, consequently, alter the channel surface potential. Changes in the potential within the formed monolayer close to the channel alter the source-drain current and, consequently, the transistor threshold (turn on) voltage.

The Scent Fingerprint of Hepatocarcinoma: In-Vitro Metastasis Prediction with Volatile Organic Compounds (VOCs)

Authors: Amal, H.; Ding, L.; Liu, B. B.; Tisch, U.; Xu, Z. Q.; Shi, D. Y.; Zhao, Y.; Chen, J.; Sun, R.; Liu, H.; Ye, S. L.; Tang, Z. Y.; Haick, H.

Years: 2012

Published in: Int. J. Nanomedicine, 7, 4135–4146

BACKGROUND:
Hepatocellular carcinoma (HCC) is a common and aggressive form of cancer. Due to a high rate of postoperative recurrence, the prognosis for HCC is poor. Subclinical metastasis is the major cause of tumor recurrence and patient mortality. Currently, there is no reliable prognostic method of invasion.
AIM:
To investigate the feasibility of fingerprints of volatile organic compounds (VOCs) for the in-vitro prediction of metastasis.
METHODS:
Headspace gases were collected from 36 cell cultures (HCC with high and low metastatic potential and normal cells) and analyzed using nanomaterial-based sensors. Predictive models were built by employing discriminant factor analysis pattern recognition, and the classification success was determined using leave-one-out cross-validation. The chemical composition of each headspace sample was studied using gas chromatography coupled with mass spectrometry (GC-MS).
RESULTS:
Excellent discrimination was achieved using the nanomaterial-based sensors between (i) all HCC and normal controls; (ii) low metastatic HCC and normal controls; (iii) high metastatic HCC and normal controls; and (iv) high and low HCC. Several HCC-related VOCs that could be associated with biochemical cellular processes were identified through GC-MS analysis.
CONCLUSION:
The presented results constitute a proof-of-concept for the in-vitro prediction of the metastatic potential of HCC from VOC fingerprints using nanotechnology. Further studies on a larger number of more diverse cell cultures are needed to evaluate the robustness of the VOC patterns. These findings could benefit the development of a fast and potentially inexpensive laboratory test for subclinical HCC metastasis

Ultrasensitive Silicon Nanowire for Real-World Gas Sensing: Noninvasive Diagnosis of Cancer from Breath Volatolome

Authors: Shehada, N.; Brönstrup, G.; Funka, K.; Christiansen, S.; Leja, M.; Haick, H.

Years: 2015

Published in: Nano Lett., 15 (2), 1288–1295

We report on an ultrasensitive, molecularly modified silicon nanowire field effect transistor that brings together the lock-and-key and cross-reactive sensing worlds for the diagnosis of (gastric) cancer from exhaled volatolome. The sensor is able to selectively detect volatile organic compounds (VOCs) that are linked with gastric cancer conditions in exhaled breath and to discriminate them from environmental VOCs that exist in exhaled breath samples but do not relate to the gastric cancer per se. Using breath samples collected from actual patients with gastric cancer and from volunteers who do not have cancer, blind analysis validated the ability of the reported sensor to discriminate between gastric cancer and control conditions with >85% accuracy, irrespective of important confounding factors such as tobacco consumption and gender. The reported sensing approach paves the way to use the power of silicon nanowires for simple, inexpensive, portable, and noninvasive diagnosis of cancer and other disease conditions.