Fan-Gang Tseng

Tri-functionalization of mesoporous silica nanoparticles for comprehensive cancer theranostics—the trio of imaging, targeting and therapy

In this work we report the development of the tri-functionalized mesoporous silica nanoparticles (MSNs) for use as theranostic compounds that orchestrate the trio of imaging, target and therapy in a single particle. The MSNs are functionalized in sequence with (1) contrast agents that enable traceable imaging of particle targeting, (2) drug payloads for therapeutic intervention and, (3) biomolecular ligands for highly-targeted particle delivery. Traceable imaging of nanoparticles was accomplished by directly incorporating a near-infrared (NIR) fluorescent contrast agent, ATTO647N, into the silica framework of MSNs, to exploit the relative transparency of most tissues at NIR wavelengths and maximize MSN surface area available for the subsequent conjugating drugs and targeting ligands. An oxygen-sensing, palladium-porphyrin based photosensitizer (Pd-porphyrin; PdTPP) was incorporated into the MSNs nanochannels, to enable photodynamic therapy (PDT). cRGDyK peptides, tiling the outermost surfaces of MSNs, were used for targeting the overexpressed αvβ3 integrins of cancer cells, and to ensure the internalization of the photosensitizer PdTPP. In vitro cell evaluation of the theranostic platform demonstrated not only excellent targeting specificity and minimal collateral damage, but highly potent therapeutic effect as well.

Mesoporous silica nanoparticles functionalized with an oxygen-sensing probe for cell photodynamic therapy: potential cancer theranostics

Functionalization of mesoporous silica nanoparticles (MSNs) with Pd-porphyrins for cancer cell photodynamic therapy is reported. The composite platform, MSN–PdTPP, expands the role of Pd-porphyrins from their routine use as phosphorescence probes for oxygen sensing/imaging (diagnostics) to that of novel nano-photosensitizers for cancer cell phototherapy (therapeutics). The utility of MSN–PdTPP in the phototherapeutic treatment of MDA-MB-231 breast cancer cells is also evaluated, suggesting it is a promising cancer theranostic platform.

Microfluidic Systems for Biosensing

In the past two decades, Micro Fluidic Systems (MFS) have emerged as a powerful tool for biosensing, particularly in enriching and purifying molecules and cells in biological samples. Compared with conventional sensing techniques, distinctive advantages of using MFS for biomedicine include ultra-high sensitivity, higher throughput, in-situ monitoring and lower cost. This review aims to summarize the recent advancements in two major types of micro fluidic systems, continuous and discrete MFS, as well as their biomedical applications. The state-of-the-art of active and passive mechanisms of fluid manipulation for mixing, separation, purification and concentration will also be elaborated. Future trends of using MFS in detection at molecular or cellular level, especially in stem cell therapy, tissue engineering and regenerative medicine, are also prospected.

A monolithically three-dimensional flow-focusing device for formation of single/double emulsions in closed/open microfluidic systems

This paper proposes a design concept and fabrication method of a planar three-dimensional (3D) microfluidic flow-focusing device (MFFD) that can produce monodisperse single/double emulsions in a closed/open microfluidic system. The device consists of three layers of SU-8 resist structures to form coaxial embedded orifices at the center of the microchannel with dimensions ranging from 50 µm to 200 µm by means of the black photoresist shadow method. Two or three immiscible fluids can be focused through the coaxial orifices, producing monodispersed droplets with a coefficient of variance (CV) of less than 4.1%. At the orifice, the inner liquid thread stays confined to the central axis of the microchannel, surrounded by the continuous phase. As the dispensed phase (inner fluid thread) does not wet channel walls, our proposed 3D MFFD can produce single emulsions for both water-in-oil (W/O) and oil-in-water (O/W) droplets utilizing the same device. The droplet diameter ranges from 50 µm to 300 µm. Also, double emulsions containing one to several internal droplets were successfully produced in the closed channel configuration. In addition, we demonstrated for the first time the feasibility of forming W/O droplets and polymer particles in an open channel configuration by withdrawing the fluid from the outlet channel. W/O droplets and polymer particles, smaller than 10 µm and 40 µm, respectively, were successfully produced. In contrast to the closed channel configuration where the droplet size decreases with an increasing flow rate, in an open channel configuration, the droplet size increases with an increasing withdrawal rate. The unique fabrication of the monolithic 3D MFFD device utilizing SU-8 resist overcomes problems regarding orifice sizes/shapes, alignment and assembly for current axisymmetric flow-focusing devices (AFFD) based on capillary microtubes, and provides flexibility for the future development of an integrated miniaturized lab-on-a-chip microsystem.

Spontaneous high-speed transport of subnanoliter water droplet on gradient nanotextured surfaces

We present water droplets that undergo spontaneous self-directed motion upon contact with a chemically patterned nanotextured surface with wedge-shaped gradient. The surface exhibits two distinct wetting properties and low hysteresis. The droplet velocity depends on the droplet position and gradient angle. A wide range of droplet volume can be transported and a droplet velocity as high as 0.5 m/s has been achieved herein. Ascension of water droplets with all-round acclivity and a subnanoliter droplet movement were also demonstrated. We conclude that it is the combination of surface tension gradient and nanowetting actuation that governs the droplet motion.

Application of 3D glycerol-compensated inclined-exposure technology to an integrated optical pick-up head

This paper proposes a novel method for integrating inclined mirrors with precise angles and smooth surfaces in on-chip Fresnel lens optical pick-up-head applications. A glycerol-compensated inclined-exposure technology was adopted for 45? mirror pair fabrication. This technology can fabricate 19?90? inclined structures onto SU-8 negative tone resist with thickness from 100 to 1000 ?m. Glycerol is employed as an index matching material during exposure to compensate for the refractive index difference between the air and SU8, thus extending the possible inclined angles from 54? (in air) down to 19? (in glycerol). To eliminate reflected induced patterns, CK-6020L resist is employed as an antireflection layer. The surface roughness, measured by AFM, is below 7 nm for various inclined angles. Device fabrication has been successfully completed and test results demonstrated a functional VCSEL (vertical cavity surface emitting laser) beam focusing on a 5 ?m spot. Further beam size reduction into the sub-micrometer range requires an objective lens with high numerical aperture, which is not within the scope of this paper. The fabricated optical components are robust and accurately aligned. This new integrated approach provides an easy and low-cost fabrication method for optical pick-up heads eliminating the need for manual assembly.

A high-resolution high-frequency monolithic top-shooting microinjector free of satellite drops - part II: fabrication, implementation, and characterization

For pt. I, see ibid., vol. 11, no. 5, p. 427-36 (2002). Describes the fabrication, implementation and characterization of a thermal driven microinjector, featuring a bubble check valve and monolithic fabrication. Microfabrication of this microinjector is based on bulk/surface-combined micromachining of the silicon wafer, free of the bonding process that is commonly used in the fabrication of commercial printing head, so that even solvents and fuels can be ejected. Droplet ejection sequences of two microinjectors have been studied along with a commercial inkjet printhead for comparison. The droplet ejection of our microinjector with 10 /spl mu/m diameter nozzle has been characterized at a frequency over 35 kHz, at least 3 times higher than those of commercial counterparts. The droplet volume from this device is smaller than 1 pl, 10 times smaller than those of commercial inkjets employed in the consumer market at the time of testing. Visualization results have verified that our design, although far from being optimized, operates in the frequency several times higher than those of commercial products and reduces the crosstalk among neighboring chambers.

Mechanical strength and interfacial failure analysis of cantilevered SU-8 microposts

This paper reports the study of both the mechanical strength and interfacial failure of cantilevered SU-8 microposts fabricated on silicon substrates. An ultra-precision instrument was developed to simultaneously measure both the displacement and resultant force of specially designed SU-8 microposts under a static bending load increasing up to an interfacial fracture. Experimental results were presented for two sets of SU-8 microposts with different geometry, one with a circular cross-section and the other with a square cross-section, both having an aspect ratio larger than 1. Shear failure stresses of both circular and square microposts were estimated to be approximately 6.53 MPa ± 4.2% and 6.83 MPa ± 9.7%, respectively. The failure regions were characterized by a scanning electron microscope to determine the failure mechanism. Our experiments showed that the hardness and Youngs modulus of SU-8 decreased with increasing penetration depth, and both quantities are sensitive to loading/unloading speeds.

Visualizing dynamics of sub-hepatic distribution of nanoparticles using intravital multiphoton fluorescence microscopy.

Nanoparticles that do not undergo renal excretion or in vivo degradation into biocompatible debris often accumulate in the reticuloendothelial system, also know as the mononuclear phagocyte system, with undesired consequences that limit their clinical utility. In this work, we report the first application of intravital multiphoton fluorescence microscopy to dynamically track the hepatic metabolism of nanoparticles with subcellular resolution in real time. Using fluorescently labeled mesoporous silica nanoparticles (MSNs) in mice as a prototypical model, we observed significant hepatocyte uptake of positively charged, but not negatively charged, moieties. Conversely, in vivo imaging of negatively charged, but not positively charged, MSNs reveals an overwhelming propensity for the formers rapid uptake by Kupffer cells in liver sinusoids. Since the only prerequisite for these studies was that nanoparticles are fluorescently labeled and not of a specific composition or structure, the techniques we present can readily be extended to a wide variety of nanoparticle structures and surface modifications (e.g., shape, charge, hydrophobicity, PEGylation) in the preclinical assessment and tailoring of their hepatotoxicities and clearances.

Substrate curvature gradient drives rapid droplet motion.

Making liquid droplets move spontaneously on solid surfaces is a key challenge in lab-on-chip and heat exchanger technologies. The best-known mechanism, a wettability gradient, does not generally move droplets rapidly enough and cannot drive droplets smaller than a critical size. Here we report how a curvature gradient is particularly effective at accelerating small droplets, and works for both hydrophilic and hydrophobic surfaces. Experiments for water droplets on tapered surfaces with curvature radii in the sub-millimeter range show a maximum speed of 0.28 m/s, two orders of magnitude higher than obtained by wettability gradient. We show that the force exerted on a droplet scales as the surface curvature gradient. Using molecular dynamics simulations, we observe nanoscale droplets moving spontaneously at over 100 m/s on tapered surfaces.