Hsian-Rong Tseng

A 160-kilobit molecular electronic memory patterned at 10 11 bits per square centimetre

The primary metric for gauging progress in the various semiconductor integrated circuit technologies is the spacing, or pitch, between the most closely spaced wires within a dynamic random access memory (DRAM) circuit. Modern DRAM circuits have 140 nm pitch wires and a memory cell size of 0.0408 μm2. Improving integrated circuit technology will require that these dimensions decrease over time. However, at present a large fraction of the patterning and materials requirements that we expect to need for the construction of new integrated circuit technologies in 2013 have ‘no known solution’. Promising ingredients for advances in integrated circuit technology are nanowires, molecular electronics and defect-tolerant architectures, as demonstrated by reports of single devices and small circuits. Methods of extending these approaches to large-scale, high-density circuitry are largely undeveloped. Here we describe a 160,000-bit molecular electronic memory circuit, fabricated at a density of 1011 bits cm-2 (pitch 33 nm; memory cell size 0.0011 μm2), that is, roughly analogous to the dimensions of a DRAM circuit projected to be available by 2020. A monolayer of bistable, [2]rotaxane molecules served as the data storage elements. Although the circuit has large numbers of defects, those defects could be readily identified through electronic testing and isolated using software coding. The working bits were then configured to form a fully functional random access memory circuit for storing and retrieving information.

Two-Dimensional Molecular Electronics Circuits

Addressing an array of bistable [2]rotaxanes through a two-dimensional crossbar arrangement provides the device element of a current-driven molecular electronic circuit. The development of the [2]rotaxane switches through an iterative, evolutionary process is described. The arrangement reported here allows both memory and logic functions to use the same elements.

Highly Efficient Capture of Circulating Tumor Cells by Using Nanostructured Silicon Substrates with Integrated Chaotic Micromixers

Metastases are the most common cause of cancer-related death in patients with solid tumors.[1–4] A considerable body of evidence indicates that tumor cells are shed from a primary tumor mass at the earliest stages of malignant progression[5–7]. These ‘break-away’ circulating tumor cells (CTCs)[8–11] enter the blood stream and travel to different tissues of the body, as a critical route for cancer metastasis. The current gold standard for determining tumor status requires invasive biopsy and subsequent genetic and proteomic analysis of biopsy samples. Alternatively, CTC measurement and analysis can be regarded as a “liquid biopsy” of the tumor, providing insight into tumor biology in the critical window where intervention could actually make a difference. However, detection and characterization of CTCs has been technically challenging due to their extremely low number in the bloodstream. CTCs are often found in the blood of patients with metastatic cancer (only up to hundreds of cells/mL) whereas common blood cells exist in high numbers (>109 cells/mL). Over the past decade, a diverse suite of technologies[8, 12–17] have been evolving to meet the challenge of counting and isolating CTCs from patient blood samples. Many employ different enrichment mechanisms such as immunomagnetic separation based on capture agent-labeled magnetic beads,[8, 16] microfluidics-based technologies[12, 14, 17] that enhance cell-surface contacts, and microfilter devices[13] that isolate CTCs based on size difference. The sensitivity of these emerging technologies, which is critical to their clinical utility for detecting early cancer progression (e.g., tumor invasion of vascular systems), relies on the degree of enrichment of CTCs.

Multistep synthesis of a radiolabeled imaging probe using integrated microfluidics.

Microreactor technology has shown potential for optimizing synthetic efficiency, particularly in preparing sensitive compounds. We achieved the synthesis of an [18F]fluoride-radiolabeled molecular imaging probe, 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG), in an integrated microfluidic device. Five sequential processes—[18F]fluoride concentration, water evaporation, radiofluorination, solvent exchange, and hydrolytic deprotection—proceeded with high radio-chemical yield and purity and with shorter synthesis time relative to conventional automated synthesis. Multiple doses of [18F]FDG for positron emission tomography imaging studies in mice were prepared. These results, which constitute a proof of principle for automated multistep syntheses at the nanogram to microgram scale, could be generalized to a range of radiolabeled substrates.

Three-Dimensional Nanostructured Substrates toward Efficient Capture of Circulating Tumor Cells

During the progression of metastasis, cancer cells detach from the solid primary tumor, enter the blood stream, and travel to different tissues of the body. These breakaway cancer cells in the peripheral blood are known as circulating tumor cells (CTCs).[1] In addition to conventional diagnostic imaging and serum marker detection, quantification of CTCs in patient blood provides new and valuable information about managing cancer.[2–5] Over the past decade, CTC counting has been used for examining cancer metastasis, predicting patient prognosis, and monitoring the therapeutic outcomes of cancer.[6] However, isolation of CTCs has been technically challenging due to the extremely low abundance (a few to hundreds per milliliter) of CTCs among a large number of hematologic cells in the blood (109 mL−1).[4, 7, 8] Several technology platforms for isolating/counting CTCs have been developed with strategies that involve immunomagnetic beads or microfluidic devices.[3, 4,9, 10] The former utilizes capture-agent-coated magnetic beads to immunologically recognize CTCs in the blood, followed by magnetic isolation. However, these bead-based approaches are limited by their low CTC-capture yield and purity. Recently, a number of microfluidic technologies[9, 10] has been established for capturing viable CTCs from whole-blood samples with improved efficiency and selectivity compared to the bead-based approach.[3, 7] While different device architectures were applied in these CTC-sorting microchips, the improved CTC-capture efficiencies were achieved by increasing CTC/substrate contact frequency and duration.

Photothermal effects of supramolecularly assembled gold nanoparticles for the targeted treatment of cancer cells.

Noble-metal nanostructures with unique photophysical properties have been considered as prime candidate agents for the photothermal treatment of cancer.[1–4] Typically, the photothermal properties of these nanostructures can be controlled by manipulating their sizes and shapes.[4,5] Over the past decade, significant endeavors have been devoted to the production of a variety of gold nanostructures, such as nanoparticles,[6,7] nanoshells,[8–10] nanorods,[11,12] and nanocages,[5,13,14] which are able to overcome limitations of organic-dye-based photothermal agents,[7] such as low light absorption and undesired photobleaching. For sufficient energy to be harvested/generated to damage tumor cells, the size of these nanostructure-based agents are required in the range of tens to hundreds nm.[15] However, the relatively “large” size of the agents often leads to poor bioclearance (i.e., accumulation in the liver, spleen, and kidneys), which is a major obstacle to their in vivo application.[16–18] Alternatively, the photophysical properties of noble-metal nanostructures can be altered systematically by the formation of aggregates through self-assembly.[19–30] The antibody-assisted aggregation of Au nanoparticles on cell membranes or in intracellular environments led to the enhancement of photothermal performance[31] as a result of the collective effects[32,33] associated with the assembled structures. Therefore, the self-assembly of small noble-metal building blocks, that is, noble-metal colloids with diameters of less than 8 nm[16–18] (compatible with renal clearance) would be a promising approach toward a new class of noble-metal photothermal agents.

A nanomechanical device based on linear molecular motors

An array of microcantilever beams, coated with a self-assembled monolayer of bistable, redox-controllable [3]rotaxane molecules, undergoes controllable and reversible bending when it is exposed to chemical oxidants and reductants. Conversely, beams that are coated with a redox-active but mechanically inert control compound do not display the same bending. A series of control experiments and rational assessments preclude the influence of heat, photothermal effects, and pH variation as potential mechanisms of beam bending. Along with a simple calculation from a force balance diagram, these observations support the hypothesis that the cumulative nanoscale movements within surface-bound “molecular muscles” can be harnessed to perform larger-scale mechanical work.

Capture and Stimulated Release of Circulating Tumor Cells on Polymer‐Grafted Silicon Nanostructures

A platform for capture and release of circulating tumor cells is demonstrated by utilizing polymer grafted silicon nanowires. In this platform, integration of ligand-receptor recognition, nanostructure amplification, and thermal responsive polymers enables a highly efficient and selective capture of cancer cells. Subsequently, these captured cells are released upon a physical stimulation with outstanding cell viability.

Supramolecular approach for preparation of size controllable nanoparticles

A supramolecular approach has been developed for the preparation of supramolecular nanoparticles (SNPs) with variable sizes (30-450 nm) from three different molecular building blocks using a cyclodextrin/adamantane recognition system. Positron emission tomography (PET) was employed to study the biodistribution and lymph node drainage of the SNPs in mice. The sizes of the SNPs affect their in vivo characteristics (see picture).

Specific Capture and Release of Circulating Tumor Cells Using Aptamer‐Modified Nanosubstrates

Circulating tumor cells (CTCs)[1] are cancer cells that have propagated from tumors, spreading into the bloodstream as the cellular origin of fatal metastasis. Besides conventional diagnostic approaches (e.g., tumor biopsy, anatomical/molecular imaging and serum marker detection), detecting CTCs in peripheral blood is of prognostic value in different types of solid tumors, especially for predicting patient survival. The fact is that CTC detection have been technically challenging because of the extremely low abundance (a few to hundreds per mL) of CTCs among a high number (109 cells mL-1) of hematologic cells.[2] Over the past decade, a diversity of diagnostic technologies has been demonstrated for CTC detection using different working mechanisms. The current FDA-cleared CellSearch™ Assay is based on immunomagnetic separation of CTCs. Due to its unsatisfactory efficiency and high cost, researchers have been exploiting new technologies,[3] e.g., flow cytometry, size-based filtration systems and microfluidic devices that may offer improved sensitivity and reduced cost for CTC detection. In addition to the prognostic utility of CTC-based diagnostics, it is conceivable that the molecular signatures and functional readouts derived from CTCs will shed much valuable insight into tumor biology during the critical window where therapeutic intervention could make a significant difference.