A Novel Blood-Based Colorectal Cancer Diagnostic Technology Using Electrical Detection of Colon Cancer Secreted Protein-2.

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide, which may be effectively reduced by early screening. Colon cancer secreted protein-2 (CCSP-2) is a promising blood marker for CRC. An electric-field effect colorectal sensor (E-FECS), an ion-sensitive field-effect transistor under dual gate operation with nanostructure is developed, to quantify CCSP-2 directly from patient blood samples. The sensing performance of the E-FECS is verified in 7 controls and 7 CRC samples, and it is clinically validated on 30 controls, 30 advanced adenomas, and 81 CRC cases. The concentration of CCSP-2 is significantly higher in plasma samples from CRC and advanced adenoma compared with controls (both P < 0.001). Sensitivity and specificity for CRC versus controls are 44.4% and 86.7%, respectively (AUC of 0.67), and 43.3% and 86.7%, respectively, for advanced adenomas (AUC of 0.67). CCSP-2 detects a greater number of CRC cases than carcinoembryonic antigen does (45.6% vs 24.1%), and the combination of the two markers detects an even greater number of cases (53.2%). The E-FECS system successfully detects CCSP-2 in a wide range of samples including early stage cancers and advanced adenoma. CCSP-2 has potential for use as a blood-based biomarker for CRC.

Fully Packaged Portable Thin Film Biosensor for the Direct Detection of Highly Pathogenic Viruses from On-Site Samples.

The thin film transistor (TFT) is a promising biosensor system with great sensitivity, label-free detection, and a quick response time. However, even though the TFT sensor has such advantageous characteristics, the disadvantages hamper the TFT sensor's application in the clinical field. The TFT is susceptible to light, noise, vibration, and limited usage, and this significantly limits its on-site potential as a practical biosensor. Herein, we developed a fully packaged, portable TFT electrochemical biosensor into a chip form, providing both portability through minimizing the laboratory equipment size and multiple safe usages by protecting the semiconductor sensor. Additionally, a safe environment that serves as a miniature probe station minimizes the previously mentioned disadvantages, while providing the means to properly link the TFT biosensor with a portable analyzer. The biosensor was taken into a biosafety level 3 (BSL-3) laboratory setting to analyze highly pathogenic avian influenza virus (HPAIV) samples. This virus quickly accumulates within a host, and therefore, early stage detection is critical to deterring the further spread of the deadly disease to other areas. However, current on-site methods have poor limits of detection (105-106 EID50/mL), and because the virus has low concentration in its early stages, it cannot be detected easily. We have compared the sample measurements from our device with virus concentration data obtained from a RT-PCR (virus range: 100-104 EID50/mL) and have identified an increasing voltage signal which corresponds to increasing virus concentration.

Field-Effect Biosensors for On-Site Detection: Recent Advances and Promising Targets.

There is an explosive interest in the immediate and cost-effective analysis of field-collected biological samples, as many advanced biodetection tools are highly sensitive, yet immobile. On-site biosensors are portable and convenient sensors that provide detection results at the point of care. They are designed to secure precision in highly ionic and heterogeneous solutions with minimal hardware. Among various methods that are capable of such analysis, field-effect biosensors are promising candidates due to their unique sensitivity, manufacturing scalability, and integrability with computational circuitry. Recent developments in nanotechnological surface modification show promising results in sensing from blood, serum, and urine. This report gives a particular emphasis on the on-site efficacy of recently published field-effect biosensors, specifically, detection limits in physiological solutions, response times, and scalability. The survey of the properties and existing detection methods of four promising biotargets, exosomes, bacteria, viruses, and metabolites, aims at providing a roadmap for future field-effect and other on-site biosensors.

Self-Normalized Detection of ANXA3 from Untreated Urine of Prostate Cancer Patients without Digital Rectal Examination.

A noninvasive quantitative assay that is capable of identifying prostate cancer biomarkers in untreated urine is an attractive diagnosis tool, but this method is subject to various obstacles. Difficulties presented by untreated urine include varying salt concentrations, and pH levels that may be different even though they are from the same patient. Untreated urine also presents interference from other biomolecules and possesses a fewer number of cancer biomarkers than can be found in serum. As a result, urine preconditioning processes and digital rectal examination (DRE) to increase biomarker secretion are mandatory in current urine assays. To address these challenges, an ion-responsive urine sensor (IRUS) that measures differential electrical signals is proposed as a self-normalized detection method. The proposed IRUS is based on a FET biosensor with a disposable sensing gate and has the capability to detect the prostate cancer antigen ANXA3 in untreated patient urine. The IRUS can detect ANXA3 at <1 fg mL-1 with high reliability. In addition, it is found that ANXA3 levels in urine show clinically significant correlation with real tumor volumes. This paper provides a guideline in developing a clinically ready accurate noninvasive platform, which is capable of predicting prostate cancer using untreated urine without DRE.

Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications.

Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field.

Detection of Avian Influenza Virus from Cloacal Swabs Using a Disposable Well Gate FET Sensor.

Current methods to detect avian influenza viruses (AIV) are time consuming and lo inw sensitivity, necessitating a faster and more sensitive sensor for on-site epidemic detection in poultry farms and urban population centers. This study reports a field effect transistor (FET) based AIV sensor that detects nucleoproteins (NP) within 30 minutes, down to an LOD of 103 EID50 mL-1 from a live animal cloacal swab. Previously reported FET sensors for AIV detection have not targeted NPs, an internal protein shared across multiple strains, due to the difficulty of field-effect sensing in a highly ionic lysis buffer. The AIV sensor overcomes the sensitivity limit with an FET-based platform enhanced with a disposable well gate (DWG) that is readily replaceable after each measurement. In a single procedure, the virus-containing sample is immersed in a lysis buffer mixture to expose NPs to the DWG surface. In comparison with commercial AIV rapid kits, the AIV sensor is proved to be highly sensitive, fast, and compact, proving its potential effectiveness as a portable biosensor.

A strategy to minimize the sensing voltage drift error in a transistor biosensor with a nanoscale sensing gate.

An ion-sensitive field-effect transistor (ISFET) biosensor is thought to be the center of the next era of health diagnosis. However, questions are raised about its functions and reliability in liquid samples. Consequently, real-life clinical applications are few in number. In this study, we report a strategy to minimize the sensing signal drift error during bioanalyte detection in an ISFET biosensor. A nanoscale SnO2 thin film is used as a gate oxide layer (GOL), and the surface of the GOL is chemically modified for improving bioanalyte-specific binding and for reducing undesirable ion reactions in sample solutions. The ISFET biosensor with surface-modified GOL shows significantly reduced sensing signal error compared with an ISFET with bare GOL in both diluted and undiluted phosphate buffered saline solutions.

Highly sensitive detection of protein biomarkers via nuclear magnetic resonance biosensor with magnetically engineered nanoferrite particles.

Magnetic-based biosensors are attractive for on-site detection of biomarkers due to the low magnetic susceptibility of biological samples. Here, we report a highly sensitive magnetic-based biosensing system that is composed of a miniaturized nuclear magnetic resonance (NMR) device and magnetically engineered nanoferrite particles (NFPs). The sensing performance, also identified as the transverse relaxation (R2) rate, of the NMR device is directly related to the magnetic properties of the NFPs. Therefore, we developed magnetically engineered NFPs (MnMg-NFP) and used them as NMR agents to exhibit a significantly improved R2 rate. The magnetization of the MnMg-NFPs was increased by controlling the Mn and Mg cation concentration and distribution during the synthesis process. This modification of the Mn and Mg cation directly contributed to improving the R2 rate. The miniaturized NMR system, combined with the magnetically engineered MnMg-NFPs, successfully detected a small amount of infectious influenza A H1N1 nucleoprotein with high sensitivity and stability.

Magnetically softened iron oxide (MSIO) nanofluid and its application to thermally-induced heat shock proteins for ocular neuroprotection.

Magnetically softened iron oxide (MSIO) nanofluid, PEGylated (Mn0.5Zn0.5)Fe2O4, was successfully developed for local induction of heat shock proteins (HSPs) 72 in retinal ganglion cells (RGCs) for ocular neuroprotection. The MSIO nanofluid showed significantly enhanced alternating current (AC) magnetic heat induction characteristics including exceptionally high SLP (Specific Loss Power, > 2000 W/g). This phenomenon was resulted from the dramatically improved AC magnetic softness of MSIO caused by the magnetically tailored Mn(2+) and Zn(2+) distributions in Fe3O4. In addition, the MSIO nanofluid with ultra-thin surface coating layer thickness and high monodispersity allowed for a higher cellular uptake up to a 52.5% with RGCs and enhancing "relaxation power" for higher AC heating capability. The RGCs cultured with MSIO nanofluid successfully induced HSPs 72 by magnetic nanofluid hyperthermia (MNFH). Moreover, it was interestingly observed that systematic control of "AC magnetically-induced heating up rate" reaching to a constant heating temperature of HSPs 72 induction allowed to achieve maximized induction efficiency at the slowest AC heating up rate during MNFH. In addition to in-vitro experimental verification, the studies of MSIO infusion behavior using animal models and a newly designed magnetic coil system demonstrated that the MSIO has promising biotechnical feasibility for thermally-induced HSPs agents in future glaucoma clinics.

Modified MgFe2O4 Ferrimagnetic Nanoparticles to Improve Magnetic and AC Magnetically-Induced Heating Characteristics for Hyperthermia.

A ferrimagnetic nanoparticle with a smaller size, a narrower size distribution, and a higher ac heat generation ability has been still studied for intra-arterial or intra-tumoral hyperthermia. In this study, we manipulate the calcining temperature in the range of 400-600 degrees C to modify MgFe2O4 ferrimagnetic nanoparticles (FMNPs) during modified sol-gel process. The modified MgFe2O4 FMNPs have well controlled with small size and narrow size distribution, so that their magnetic and ac magnetically-induced heating characteristics are significantly improved. In particular, MgFe2O4 nanoparticles synthesized at the calcining temperature of 600 degrees C and sintering temperature of 700 degrees C show the most suitable size (58 nm ± 13 nm) and its distribution (22%) resulting in the highest ac magnetically-induced heating temperature (T(AC,mag), ΔT = 93 degrees C) and SLP (Specific Loss Power, 600 W/g) at the biologically tolerable range of magnetic field (H(appl) = 140 Oe) and frequency (f(appl) = 110 kHz). It is found to be due to the improvement of magnetic softness and saturation magnetization resulting in the largest hysteresis loss power. All the results in this work clearly demonstrate that calcining process is one of the key parameters to control the proper size and size distribution for improving magnetic and ac magnetically-induced heating characteristics of MgFe2O4 FMNPs, which can be applicable to hyperthermia agents in nanomedicine.

Diagnosis of prostate cancer via nanotechnological approach.

Prostate cancer is one of the leading causes of cancer-related deaths among the Caucasian adult males in Europe and the USA. Currently available diagnostic strategies for patients with prostate cancer are invasive and unpleasant and have poor accuracy. Many patients have been overly or underly treated resulting in a controversy regarding the reliability of current conventional diagnostic approaches. This review discusses the state-of-the-art research in the development of novel noninvasive prostate cancer diagnostics using nanotechnology coupled with suggested diagnostic strategies for their clinical implication.

Electrical signaling of enzyme-linked immunosorbent assays with an ion-sensitive field-effect transistor.

Optical laboratory-based immunoassays, such as enzyme-linked immunosorbent assay (ELISA) give a high sensitivity and specificity of various fatal diseases. However, these assays are no longer efficient in on-spot diagnostics of wide-spreading and contagious infections. At this point in time, portable and handhold devices play a pivotal role in infectious diseases with quick diagnostics at or near the site of the disease propagation. In this paper, we demonstrated a novel electrical immunoassay of ELISA that was not based on optical signaling but on electrical signaling. This was done by combining an ion-sensitive field-effect transistor (ISFET) with ELISA. By harnessing the catalytic reaction of alkaline phosphatase that precipitated silver particles, we effectively overcame the chronic Debye screening length issue of the ISFET. Ultimately, small signal ranging from 1 pg/mL to 10 ng/mL was immensely amplified with the ALP label, regardless of buffer conditions. The sensor platform herein surpassed a sensing capability of conventional ELISA that is considered to have a LOD on the order of ~1 ng/mL. The results were compared with those of horseradish peroxidase label, which is generally used for optical analyses in ELISA. Our newly developed ISFET-based portable sensor holds a large potential for point-of-care tools in a variety of diseases, without being limited by the need for expensive equipment such as spectrophotometers.

Tailoring Mg(x)Mn(1-x)Fe(2)O(4) superparamagnetic nanoferrites for magnetic fluid hyperthermia applications.

A superparamagnetic nanoferrite (SPNF) with high magnetic moment, AC magnetically induced heating (AC-heating) capacity, and good biocompatibility is the most vital part of magnetic fluid hyperthermia for utilizing it in the clinics. Herein, we precisely tune magnetic properties and AC-heating characteristics of MgxMn1-xFe2O4 SPNF via chemically controlling the cations' concentration and distribution to develop a tailored MgxMn1-xFe2O4 SPNF as a potential magnetic fluid hyperthermia agent. The magnetic and AC-heating characteristics of the tailored MgxMn1-xFe2O4 SPNF are strongly dependent on the Mg/Mn cations' concentration and distribution, and Mg0.285Mn0.715Fe2O4 SPNF exhibits the highest saturation magnetization and AC-heating capacity as well as high biocompatibility.

Physical contribution of Néel and Brown relaxation to interpreting intracellular hyperthermia characteristics using superparamagnetic nanofluids.

In this work, the AC magnetically-induced heating characteristics of various viscous nanofluids with either soft ferrite (Fe3O4) or hard ferrite (CoFe2O4) superparamagnetic nanoparticles (SPNPs) were investigated to empirically and physically interpret the contribution of "Néel relaxation loss power, P(Néel relaxation loss)," or "Brown relaxation loss power, P(Brown relaxation loss)," to the total AC heat generation of intracellular hyperthermia or in-vivo hyperthermia. It was found that the contribution of P(Brown relaxation loss) to the total AC heating power, P(totaI), and the specific loss power (SLP) was severely affected by the surrounding environment (or in-vivo environment) while the contribution of P(Néel relaxation loss) to the P(total) was independent of the variation of surrounding environment. Furthermore, all the theoretical and experimental results strongly suggested that highly efficacious intracellular hyperthermia (or in-vivo hyperthermia) modality can be achieved by enhancing the P(Néel relaxation loss) rather than the P(Brown relaxation loss) of SPNP agents in nanofluids.

Engineered superparamagnetic Mn0.5Zn0.5Fe2O4 nanoparticles as a heat shock protein induction agent for ocular neuroprotection in glaucoma.

Ocular neuroprotection induced by localized heat shock proteins (HSPs) has been paid considerable attention as an efficacious treatment modality for glaucoma. However, the current clinical approaches to induce HSPs in the retinal ganglion cells (RGCs) are limited due to undesirable side effects. Here, we present that the induction of HSPs by local magnetic hyperthermia using engineered superparamagnetic Mn(0.5)Zn(0.5)Fe(2)O(4) nanoparticle agents (EMZF-SPNPAs) with a 5.5 nm mean particle size is promisingly feasible for a physiologically tolerable ocular neuroprotection modality. The sufficiently high specific absorption rate (SAR) (∼256.4 W/g in an agar solution) achieved at the biologically safe range of applied AC magnetic field and frequency as well as the superior biocompatibility of EMZF-SPNPA, which were confirmed from both in-vitro and in-vivo animal pilot studies, allowing it to be considered as a potential localized HSPs agent. Furthermore, the successful demonstration of a newly designed infusion technique, which diffuses the EMZF-SPNPAs through the vitreous body to the retina in a rat eye, more strongly verified the promises of this biotechnical approach to the ocular neuroprotection modality in glaucoma clinics.

Finite size effect on hydrogen gas sensing performance in single Pd nanowires.

We present the hydrogen sensing performance of individual Pd nanowires grown by electrodeposition into nanochannels of anodized aluminum oxide (AAO) templates investigated as a function of the nanowire diameter. Four-terminal devices based on individual Pd nanowires were found to successfully detect hydrogen gas (H(2)). Our experimental results show that the H(2) sensing sensitivity increases and the response time decreases with decreasing diameter of Pd nanowires with d = 400, 200, 80 and 20 nm, due to the high surface-to-volume ratio and short diffusion paths, respectively. This is in qualitatively good agreement with simulated results obtained from a theoretical model based on a combination of the rate equation and diffusion equation.