The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

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Cancer nanomedicine: progress, challenges and opportunities.

Much has been written about theory and practice in the law, and the tension between practitioners and theorists. Judges do not cite theoretical articles often; they rarely "apply" theories to particular cases. These arguments are not revisited. Instead the Essay explores the working and interaction of theory and practice, practitioners and theorists. The Essay starts with a story about solving a legal issue using our intellectual tools - theory, practice, and their progenies: experience and "gut." Next the Essay elaborates on the nature of theory, practice, experience and "gut." The third part of the Essay discusses theories that are helpful to practitioners and those that are less helpful. The Essay concludes that practitioners theorize, and theorists practice. They use these intellectual tools differently because the goals and orientations of theorists and practitioners, and the constraints under which they act, differ. Theory, practice, experience and "gut" help us think, remember, decide and create. They complement each other like the two sides of the same coin: distinct but inseparable.

Of Theory and Practice

This thesis explores transport phenomena in nanochannels on a chip. Fundamental nanofluidic ionic studies form the basis for novel separation and preconcentration applications for proteomic purposes. The measurements were performed with 50-nm-high 1D nanochannels, which are easily accessible from both sides by two microchannels. Nanometer characteristic apertures were manufactured in the bonded structure of Pyrex-amorphous silicon – Pyrex, in which the thickness of the amorphous silicon layer serves as a spacer to define the height of the nanochannels. The geometry of the nanometer-sized apertures is well defined, which simplifies the modeling of the transport across them. Compared to biological pores, the present nanochannels in Pyrex offer increased stability. Fundamental characteristics of nanometer-sized apertures were obtained by impedance spectroscopy measurements of the nanochannel at different ionic strengths and pH values. A conductance plateau (on a log-log scale) was modeled and measured, establishing due to the dominance of the surface charge density in the nanochannels, which induces an excess of mobile counterions to maintain electroneutrality. The nanochannel conductance can be regulated at low ionic strengths by pH adjustment, and by an external voltage applied on the chip to change the zeta potential. This field-effect allows the regulation of ionic flow which can be exploited for the fabrication of nanofluidic devices. Fluorescence measurements confirm that 50-nm-high nanochannels show an exclusion of co-ions and an enrichment of counterions at low ionic strengths. This permselectivity is related to the increasing thickness of the electrical double layer (EDL) with decreasing salt concentrations, which results in an EDL overlap in an aperture if the height of the nanochannel and the thickness of the EDL are comparable in size. The diffusive transport of charged species and therefore the exclusion-enrichment effect was described with a simple model based on the Poisson-Boltzmann equation. The negatively charged Pyrex surface of the nanometer characteristic apertures can be inversed with chemical surface pretreatments, resulting in an exclusion of cations and an enrichment of anions. When a pressure gradient is applied across the nanochannels, charged molecules are electrostatically rejected at the entrance of the nanometer-sized apertures, which can be used for separation processes. Proteomic applications are presented such as the separation and preconcentration of proteins. The diffusion of Lectin proteins with different isoelectric points and very similar compositions were controlled by regulating the pH value of the buffer. When the proteins are neutral at their pI value, the diffusion coefficient is maximal because the biomolecules does not interact electrostatically with the charged surfaces of the nanochannel. This led to a fast separation of three Lectin proteins across the nanochannel. The pI values measured in this experiment are slightly shifted compared to the values obtained with isoelectric focusing because of reversible adsorption of proteins on the walls which affects the pH value in the nanochannel. An important application in the proteomic field is the preconcentration of biomolecules. By applying an electric field across the nanochannel, anionic and cationic analytes were preconcentrated on the cathodic side of the nanometer-sized aperture whereas on the anodic side depletion of ions was observed. This is due to concentration polarization, a complex of effects related to the formation of ionic concentration gradients in the electrolyte solution adjacent to an ion-selective interface. It was measured that the preconcentration factor increased with the net charge of the molecule, leading to a preconcentration factor of > 600 for rGFP proteins in 9 minutes. Such preconcentrations are important in micro total analysis systems to achieve increased detection signals of analytes contained in dilute solutions. Compared to cylindrical pores, our fabrication process allows the realization of nanochannels on a chip in which the exclusion-enrichment effect and a big flux across the nanometer-sized aperture can be achieved, showing the interest for possible micro total analysis system applications. The described exclusion-enrichment effect as well as concentration polarization play an important role in transport phenomena in nanofluidics. The appendix includes preliminary investigations in DNA molecule separation and fluorescence correlation spectroscopy measurements, which allows investigating the behavior of molecules in the nanochannel itself.

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Transport phenomena in nanofluidics

An object is to provide a semiconductor device of which a manufacturing process is not complicated and by which cost can be suppressed, by forming a thin film transistor using an oxide semiconductor film typified by zinc oxide, and a manufacturing method thereof. For the semiconductor device, a gate electrode is formed over a substrate; a gate insulating film is formed covering the gate electrode; an oxide semiconductor film is formed over the gate insulating film; and a first conductive film and a second conductive film are formed over the oxide semiconductor film. The oxide semiconductor film has at least a crystallized region in a channel region.

Semiconductor device, and manufacturing method thereof

The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies — such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs — and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.

Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies

The group III-nitrides and their alloys represent a promising system for semiconducting device applications, especially for photonic devices, because they are direct band gap semiconductors with potential light emission from ultraviolet to infrared. Growth of GaN and InN nanowires was reported by a number of groups employing mainly catalyzed vaporliquid-solid (VLS) or catalyst-free vapor-solid (VS) growths ([1], [2] and References therein). One simple, economical and very successful method to grow both types of nanowires is using hot-wall chemical vapor deposition. Understanding the electronic properties of the as-grown nanowires is a crucial step towards their implementation in useful devices. Here we summarize the electric properties of a large number of devices (field-effect transistors) that we built with nanowires grown using this simple process. Both indium nitride and gallium nitride nanowires exhibit high carrier concentrations, with mobilities limited by impurity scattering. In particular, the gallium nitride nanowires appear to grow heavily compensated, as inferred from our theoretical estimates and annealing experiments.

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Electron mobility study of hot-wall CVD GaN and InN nanowires

The present invention provides for improved antimicrobial susceptibility testing and more specifically for improved rapid antimicrobial susceptibility testing of clinical samples for efficient and versatile analysis and reliable results.

Methods for improved rapid antimicrobial susceptibility testing

Assay methods for detecting analytes in samples involving the use of nanoparticles that comprise a signal inducing agent, e.g., a transition- metal catalyst. After binding to an analyte, the nanoparticle is dissociated by a trigger to release the signal inducing agent, which releases a detectable signal via a physical or chemical reaction. Also described herein are nanoparticles, and compositions and uses thereof, where the nanoparticle comprises chemiluminophore, a chemiluminophore precursor, a soluble absorber, or a soluble absorber precursor, that effects chemical reactions that serve as signal amplifiers.

Dissociable transition-metal nanoparticles

Nanowire Field Effect Transistors have emerged as a promising technology for point-of-care application. However, their application as quantitative sensors has not been well explored. In this work we propose a calibration scheme for multiplexed nanoribbon field effect sensors by utilizing the initial current rate rather than the end point detection. A linear response of nanosensors is observed in medically relevant range of analyte concentration. Moreover, we are able to show that top-down fabrication technique yields reproducible result and devices with uniform electrical characteristics. In addition, we demonstrate that device calibration can be done by using either baseline current or device transconductance normalization.

Calibration methods for silicon nanowire BioFETs

We report electrically excited infrared emission from a single InN nanowire transistor. We report on: (1) the generation of IR emission byimpact excitation of carriers under a high electrical field, (2) the size of the fundamental band gap of InN NW by measuring its emissionspectra, (3) the observation of interband and conduction-band to conduction-band hot-carrier emission, and the carrier relaxation rate, andfinally, (4) we present evidence that suggests that the electron accumulation layer at the InN NW surface forms a surface plasmon thatcouples to and enhances radiative electron−hole pair recombination. In the past few years, we have seen intense interest focusedon inorganic nanowires (NWs) and their properties. 1-9 Particular emphasis has been placed on the photonic andopto-electronic properties of NWs. 1-9 Lasing from individualNWs, 2-3 electrically induced emission from NW-NWcontacts, 4-5 and electroluminescence 5-7 have been reported.However, not many NWs are found to luminescence becauseof surface and bulk traps that lead to nonradiative decay ofthe excitons.Semiconducting group III nitrides have been the focus ofmuch research in recent years because of their excellentinherent electronic and optoelectronic properties. In particu-lar, indium nitride (InN) was predicted to have the lowesteffective electron mass among all the III-nitride compounds,potentially leading to a high mobility semiconductor.

Eric Stern

Papers

Electron mobility study of hot-wall CVD GaN and InN nanowires

Methods for improved rapid antimicrobial susceptibility testing

Dissociable transition-metal nanoparticles

Calibration methods for silicon nanowire BioFETs

Electrically-excited Infrared Emission from InN Nanowire Transistors