A magnetically controlled MEMS device for drug delivery: design, fabrication, and testing

We report the development of a magnetically controlled drug delivery device for on-demand drug release to treat chronic diseases. The devices consist of drug-loaded micro-reservoirs (6 mm in diameter and ～550 μm in depth), sealed by magnetic PDMS (polydimethylsiloxane) membranes (? 6 mm × 40 μm) with laser-drilled apertures and actuated by an external magnetic field. We present a detailed analysis of the magnetic actuation forces and provide an estimate of the resulting membrane deflections. The reservoirs are fabricated by PDMS molding and loaded with drugs using solvent evaporation methods. Post-processing procedures using bovine serum albumin (BSA) adsorption on magnetic PDMS surfaces are carried out to modify the surface wettability and to allow water filling and dissolution of the drugs in the reservoirs. Detailed surface modification processes are described and characterized. The device demonstrates on-demand delivery of methylene blue (MB) as a model drug. Intermittent magnetic actuations of the device in a ～200 mT magnetic field show 10-fold increase in MB release compared to background release when the device is not actuated.     

微流蒸发光散射检测器的研制及评价

构建了适用于纳升级到微升级流量的毛细管分离体系的微流蒸发光散射检测器(μELSD),实现了其与毛细管液相色谱(eLC)的联用.对雾化器孔径和雾化毛细管内径、蒸发管内径和长度、光散射池尺寸、雾化毛细管位置和辅助载气流量等参数进行了优化.在最优条件下,微流蒸发光散射检测器检出限为直接进样葡萄糖1 ng(S/N＞ 10),线性范围0.01～1.0 μg,重复性好,峰面积RSD(n=6)为0.4％,峰高RSD(n=6)为0.3％.本检测器已成功应用cLC-μELSD平台,使用C18毛细管色谱柱(内径250 μm),0.1％甲酸铵溶液(pH 4.5)-甲醇(60∶40,V/V)为流动相,分离检测了3种常用甜味剂,表明本研究构建的系统可以应用于实际分离检测中,具有分析时间快、溶剂消耗量少、样品需求量小的优点.     

HPLC法测定脂质体松萝酸中松萝酸的含量

建立了HPLC测定脂质体松萝酸中药物松萝酸的方法。以Kromasil C18反相色谱柱(250 mmⅹ4.6 mm,5μm)为分离柱,流动相组成为V(甲醇)∶V(磷酸盐缓冲液(pH 5.0))=7∶3,流速1 mL/min,紫外检测,波长284 nm。松萝酸在10~50μg/mL的范围内有很好的线性关系(r=0.9994)。加样回收率为100.1%±0.6%,RSD为0.54%±0.07%。本方法适用于脂质体松萝酸中药物松萝酸的测定。     

Photomechanical Polymer Nanocomposites for Drug Delivery Devices

We demonstrate a novel structure based on smart carbon nanocomposites intended for fabricating laser-triggered drug delivery devices (DDDs). The performance of the devices relies on nanocomposites’ photothermal effects that are based on polydimethylsiloxane (PDMS) with carbon nanoparticles (CNPs). Upon evaluating the main features of the nanocomposites through physicochemical and photomechanical characterizations, we identified the main photomechanical features to be considered for selecting a nanocomposite for the DDDs. The capabilities of the PDMS/CNPs prototypes for drug delivery were tested using rhodamine-B (Rh-B) as a marker solution, allowing for visualizing and quantifying the release of the marker contained within the device. Our results showed that the DDDs readily expel the Rh-B from the reservoir upon laser irradiation and the amount of released Rh-B depends on the exposure time. Additionally, we identified two main Rh-B release mechanisms, the first one is based on the device elastic deformation and the second one is based on bubble generation and its expansion into the device. Both mechanisms were further elucidated through numerical simulations and compared with the experimental results. These promising results demonstrate that an inexpensive nanocomposite such as PDMS/CNPs can serve as a foundation for novel DDDs with spatial and temporal release control through laser irradiation.     

An improved LC-MS/MS method for quantitative determination of metolazone in human plasma and its application to a pharmacokinetic study

A simple, rapid and accurate liquid chromatography-tandem mass spectrometry method has been developed. After a liquid-liquid extraction procedure, samples were chromatographed on an Agilent TC-C(18) (150 × 4.6 mm, 5 μm) column using an isocratic elution mobile phase composed of methanol and distilled water (70:30, v/v) at a flow rate of 0.5 mL/min. After single-dose administration of 0.5, 1 and 2 mg metolazone, the t(1/2) values were 6.6 ± 2.8, 7.9 ± 1.2 and 7.6 ± 1.9 h, respectively. The pharmacokinetic parameters of multiple doses (1 mg metolazone) were as follows: t(1/2) was 8.9 ± 1.0 h; C(max) was 22.4 ± 5.0 ng/mL; and AUC(0-48) was 156.8 ± 31.6 ng h/mL.     

Development and validation of an improved method for the quantitation of sertraline in human plasma using LC-MS-MS and its application to bioequivalence studies

A rapid and sensitive LC-MS-MS method for the quantitation of sertraline in human plasma was developed and validated. Sertraline and the internal standard, telmisartan, were cleaned up by protein precipitation from 100 μL of plasma sample, and analyzed on a TC-C18 column (5 μm, 150 × 4.6 mm i.d.) using 70% acetonitrile and 30% 10 mM ammonium acetate (0.1% formic acid) as mobile phase. The method was demonstrated to be linear from 0.1 ng/mL to 50 ng/mL with the lower limit of quantitation of 0.1 ng/mL. Intra- and inter-day precision were below 4.40% and 3.55%. Recoveries of sertraline at low, medium, and high levels were 88.0 ± 2.3%, 88.2 ± 1.9%, and 90.0 ± 2.0%, respectively. The method was successfully applied to a bioequivalence study of sertraline after a single oral administration of 50 mg sertraline hydrochloride tablets.     

Stir bar sorptive extraction and comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry for ultra-trace analysis of organochlorine pesticides in river water

A method for the determination of ultra-trace amounts of organochlorine pesticides (OCPs) in river water was developed by using stir bar sorptive extraction (SBSE) followed by thermal desorption and comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry (SBSE-TD-GC×GC-HRTOF-MS). SBSE conditions such as extraction time profiles, phase ratio (β: sample volume/polydimethylsiloxane (PDMS) volume), and modifier addition, were examined. Fifty milli-liter sample including 10% acetone was extracted for 3 h using stir bars with a length of 20 mm and coated with a 0.5 mm layer of PDMS (PDMS volume, 47 μL). The stir bar was thermally desorbed and subsequently analyzed by GC×GC-HRTOF-MS. The method showed good linearity over the concentration range from 50 to 1000 pg L(-1) or 2000 pg L(-1) for all analytes, and the correlation coefficients (r(2)) were greater than 0.9903 (except for β-HCH, r(2)=0.9870). The limit of detection (LOD) ranged from 10 to 44 pg L(-1). The method was successfully applied to the determination of 16 OCPs at pg L(-1) to ng L(-1) in river water. The results agree fairly well with the values obtained by a conventional liquid-liquid extraction (LLE)-GC-HRMS (selected ion monitoring: SIM) method using large sample volume (20 L). The method also allows screening of non-target compounds, e.g. pesticides and their degradation products, polyaromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and pharmaceuticals and personal care products (PPCPs) and metabolites in the same river water sample, by using full spectrum acquisition with accurate mass in GC×GC.     

Simple replication methods for producing nanoslits in thermoplastics and the transport dynamics of double-stranded DNA through these slits

Mixed-scale nano- and microfluidic networks were fabricated in thermoplastics using simple and robust methods that did not require the use of sophisticated equipment to produce the nanostructures. High-precision micromilling (HPMM) and photolithography were used to generate mixed-scale molding tools that were subsequently used for producing fluidic networks into thermoplastics such as poly(methyl methacrylate), PMMA, cyclic olefin copolymer, COC, and polycarbonate, PC. Nanoslit arrays were imprinted into the polymer using a nanoimprinting tool, which was composed of an optical mask with patterns that were 2-7 μm in width and a depth defined by the Cr layer (100 nm), which was deposited onto glass. The device also contained a microchannel network that was hot embossed into the polymer substrate using a metal molding tool prepared via HPMM. The mixed-scale device could also be used as a master to produce a polymer stamp, which was made from polydimethylsiloxane, PDMS, and used to generate the mixed-scale fluidic network in a single step. Thermal fusion bonding of the cover plate to the substrate at a temperature below their respective T(g) was accomplished by oxygen plasma treatment of both the substrate and cover plate, which significantly reduced thermally induced structural deformation during assembly: ～6% for PMMA and ～9% for COC nanoslits. The electrokinetic transport properties of double-stranded DNA (dsDNA) through the polymeric nanoslits (PMMA and COC) were carried out. In these polymer devices, the dsDNA demonstrated a field-dependent electrophoretic mobility with intermittent transport dynamics. DNA mobilities were found to be 8.2 ± 0.7 × 10(-4) cm(2) V(-1) s(-1) and 7.6 ± 0.6 × 10(-4) cm(2) V(-1) s(-1) for PMMA and COC, respectively, at a field strength of 25 V cm(-1). The extension factors for λ-DNA were 0.46 in PMMA and 0.53 in COC for the nanoslits (2-6% standard deviation).     

A vertical microfluidic probe

Performing localized chemical events on surfaces is critical for numerous applications. We earlier invented the microfluidic probe (MFP), which circumvented the need to process samples in closed microchannels by hydrodynamically confining liquids that performed chemistries on surfaces (Juncker et al. Nat. Mater. 2005, 4, 622-628). Here we present a new and versatile probe, the vertical MFP (vMFP), which operates in the scanning mode while overcoming earlier challenges that limited the practical implementation of the MFP technology. The key component of the vMFP is the head, a microfluidic device (～1 cm(2) in area) consisting of glass and Si and having microfluidic features fabricated in-plane in the Si layer. The base configuration of the head has two micrometer-size channels that inject/aspirate liquids and terminate at the apex which is ～1 mm(2). In scanning mode, the head is oriented vertically with the apex parallel to the surface with typical spacing of 1-30 μm. Such length scales and using flow rates from nanoliters/second to microliters/second allow chemical events to be performed on surfaces with tens of picoliter quantities of reagents. Before scanning, the head is clipped on a holder for leak-free, low dead volume interface assembly, providing a simple world-to-chip interface. Surfaces are scanned by mounting the holder on a computer-controlled stage having ～0.1 μm resolution in positioning. We present detailed steps to fabricate vMFP heads having channels with dimensions from 1 μm × 1 μm to 50 μm × 50 μm for liquid localization over areas of 10-10,000 μm(2). Additionally, advanced design strategies are described to achieve high yield in fabrication and to support a broad range of applications. These include particulate filters, redundant aperture architectures, inclined flow-paths that service apertures, and multiple channels to enable symmetric flow confinement. We also present a method to characterize flow confinement and estimate the distance between the head and the surface by monitoring the evolution of a solution of fluorescently labeled antibody on an activated glass surface. This flow characterization reveals regimes of operation suitable for different surface topographies. We further integrate the dispensing of immersion liquid to the vMFP head for processing surfaces for extended periods of time (～60 min). The versatility of the vMFP is exemplified by patterning fluorescently labeled proteins, inactivation of cells using sodium hypochlorite, and staining living NIH fibroblasts with Cellomics. These applications are enabled by the compact design of the head, which provides easy access to the surface, simplifies alignment, and enables processing surfaces having dimensions from the micrometer to the centimeter scale and with large topographical variations. We therefore believe that ease-of-operation, reconfigurability, and conservative use of chemicals by the vMFP will lead to its widespread use by microtechnologists and the chemical and biomedical communities.     

Rapid and sensitive LC-MS/MS method for the determination of metoprolol in Beagle dog plasma with a simple protein precipitation treatment and its pharmacokinetic applications

A rapid LC-MS/MS method with good accuracy and sensitivity was developed and validated for the pharmacokinetics study of metoprolol (MP) in beagle dogs. The plasma samples were simply precipitated by methanol and then analyzed by LC-MS/MS. An Ultimate XB-C?? column (150 × 2.1 mm ID, 5 μm) was used for separation, with methanol-water containing 0.2% formic acid (65:35, v/v) as the mobile phase at a flow rate of 0.2 mL/min. Monitoring ions of MP and internal standard (hydroxypioglitazone) were m/z 268.1/115.6 and m/z 373.1/150.2, respectively. The linear range was 3.03-416.35 ng/mL with an average correlation coefficient of 0.9996, and the limit of quantification was 3.03 ng/mL. The intra- and inter-day precision was less than 15%. At low, middle and high concentrations, the recovery, the matrix effect and the accuracy was in the range of 76.06%-95.25%, 93.67%-104.19% and 95.20%-99.96% respectively. The method was applied for the pharmacokinetics study of MP tartrate tablets (50 mg). The AUC(0-t), T(max) and C(max) were respectively 919.88 ± 195.67 μg/L·h, 0.96 ± 0.33 h, 349.12 ± 78.04 ng/mL.     

A μL-scale micromachined microbial fuel cell having high power density

We report a MEMS (Micro-Electro-Mechanical Systems)-based microbial fuel cell (MFC) that produces a high power density. The MFC features 4.5-μL anode/cathode chambers defined by 20-μm-thick photo-definable polydimethylsiloxane (PDMS) films. The MFC uses a Geobacter-enriched mixed bacterial culture, anode-respiring bacteria (ARB) that produces a conductive biofilm matrix. The MEMS MFC generated a maximum current density of 16,000 μA cm(-3) (33 μA cm(-2)) and power density of 2300 μW cm(-3) (4.7 μW cm(-2)), both of which are substantially greater than achieved by previous MEMS MFCs. The coulombic efficiency of the MEMS MFC was at least 31%, by far the highest value among reported MEMS MFCs. The performance improvements came from using highly efficient ARB, minimizing the impact of oxygen intrusion to the anode chamber, having a large specific surface area that led to low internal resistance.     

Determination of ipriflavone in human plasma by LC-MS and its application in a pharmacokinetic study

A sensitive liquid chromatography-mass spectrometric method was developed for the quantification of ipriflavone in human plasma. The method utilized liquid-liquid extraction of plasma with ethyl acetate. A gradient elution was performed on a Hedera ODS-2 column (150×2.1 mm i.d., 5 μm), using a mobile phase consisting of 0.1% formic acid solution and methanol at a flow rate of 0.5 mL/min. The single quadrupole mass spectrometer was operated in selected-ion monitoring mode via positive electrospray ionization interface detecting m/z 239.1 and 285.1 for ipriflavone and diazepam (the internal standard), respectively. To improve the selectivity and sensitivity, the fragment ion m/z 239.1, which was produced by in-source collision-induced dissociation, was chosen as the quantitative ion for ipriflavone. The method was fully validated and applied to a pharmacokinetic study of ipriflavone. After oral administration of a single 200 mg ipriflavone tablet, the C(max,) AUC(0-72 h) , t(1/2) and T(max) were 6.3±6.3 ng/mL, 80.0±69.1 μg h/L, 23.0±8.6 h and 3.4±2.1 h, respectively.     

On-line analysis of carbonyl compounds with derivatization in aqueous extracts of atmospheric particulate PM10 by in-tube solid-phase microextraction coupled to capillary liquid chromatography

A new device for carbonyl compounds based on coupling on-line and miniaturizing both, sample pretreatment and chromatographic separation, is reported. Two capillary columns, a GC capillary column (95% methyl-5% phenyl substituted backbone, 70 cm × 0.32 mm i.d., 3 μm film thickness) in the injection valve for in-tube solid-phase microextraction (IT-SPME) and a Zorbax SB C18 (150 mm × 0.5 mm i.d., 5 μm particle diameter) LC capillary column were employed. Different combinations of IT-SPME and derivatization using 2,4-dinitrophenylhydrazine (DNPH) were examined for mixtures containing 15 carbonyl compounds (aliphatic, aromatic and unsaturated aldehydes and ketones). A screening analysis of aqueous extracts of atmospheric particulate PM(10) was carried out. Moreover, the possibility of coupling IT-SPME and conventional liquid chromatography is also tested. Derivatization solution and IT-SPME coupled to capillary liquid chromatography provided the best results for achieving the highest sensitivity for carbonyl compounds in atmospheric particulate analysis. Detection limits (LODs) using a photodiode array detector (DAD) were ranged from 30 to 198 ng L(-1), improving markedly those LODs reported by conventional SPME-LC-DAD.     

烷基酚聚氧乙烯醚在不同液相色谱分离模式中的分离研究

考察了烷基酚聚氧乙烯醚在反相色谱、正相键合色谱、硅胶吸附色谱、体积排阻色谱4种不同液相色谱分离模式中的分离效果,分别采用Kromasil C_(18)(250 mm× 4.6 mm,5 μm)、Agilent ZORBAX NH2(250 mm× 4.6 mm,5 μm)、Waters Spherisorb S3W(150 mm×2.0 mm,3 μm)和Shodex MSpak GF-310 2D(150 mm×2.0 mm,5 μm)色谱柱,以225 nm为紫外检测波长,对不同液相色谱分离模式的流动相组成、梯度洗脱条件、柱温、流速等进行了优化,并对烷基酚聚氧乙烯醚在不同液相色谱分离模式中的保留机理进行了初步探讨.结果表明,正相键合色谱实现了烷基酚聚氧乙烯醚的最佳分离;硅胶吸附色谱和体积排阻色谱的分离效果较正相键合色谱稍差.     

Trace species detection in the near infrared using Fourier transform broadband cavity enhanced absorption spectroscopy: initial studies on potential breath analytes

Cavity enhanced absorption measurements have been made of several species that absorb light between 1.5 and 1.7 μm using both a supercontinuum source and superluminescent light emitting diodes. A system based upon an optical enhancement cavity of relatively high finesse, consisting of mirrors of reflectivity ～99.98%, and a Fourier transform spectrometer, is demonstrated. Spectra are recorded of isoprene, butadiene, acetone and methane, highlighting problems with spectral interference and unambiguous concentration determinations. Initial results are presented of acetone within a breath-like matrix indicating ppm precision at <～10 ppm acetone levels. Instrument sensitivities are sufficiently enhanced to enable the detection of atmospheric levels of methane. Higher detection sensitivities are achieved using the supercontinuum source, with a minimum detectable absorption coefficient of ～4 × 10(-9) cm(-1) reported within a 4 min acquisition time. Finally, two superluminescent light emitting diodes are coupled together to increase the wavelength coverage, and measurements are made simultaneously on acetylene, CO(2), and butadiene. The absorption cross-sections for acetone and isoprene have been measured with an instrumental resolution of 4 cm(-1) and are found to be 1.3 ± 0.1 × 10(-21) cm(2) at a wavelength of 1671.9 nm and 3.6 ± 0.2 × 10(-21) cm(2) at 1624.7 nm, respectively.     

液相色谱-电喷雾电离/离子阱质谱法分析金线莲中3-吡啶甲醇

应用现代提取技术超声-微波协同萃取金线莲中的3-吡啶甲醇,采用固相萃取技术对样品进行前处理,高效液相色谱法-电喷雾电离/离子阱质谱法(HPLC-ESI/MS)对提取物中3-吡啶甲醇进行测定和鉴别.色谱条件:Agilent TC-C₁₈色谱柱(5 μm,4.6×250 mm),流动相:甲醇-0.02 mol/L乙酸铵(5∶95,V/V),流速:1 mL/min,检测波长:260 nm.结果表明峰面积与3-吡啶甲醇在浓度1~10 μg/mL范围内呈良好线性关系.回收率在92.0%~96.2%之间,相对标准偏差为2.36%.该法简便、准确、快速.     

Integration of a macro/micro architectured compartmentalised neuronal culture device using a rapid prototyping moulding process

The rapid prototyping of a reversible and one step moulded compartmentalised neuron glass/PDMS device with a thin wall barrier directly adjacent to the reservoirs is presented. A simple moulding technique to produce these devices results in a barrier of 560 μm where the 3 μm deep by 8 μm wide channels can be reversibly fabricated in either the glass base or PDMS compartmentalised mould depending on the type of application required. Using glass substrates with commercially laser engraved microchannels, both the PDMS planar and PDMS channelled device can be easily fabricated in a standard laboratory. The compartmentalised device has several advantages including good experimental accessibility and versatility with a variety of end user applications.     

Microfluidic baker's transformation device for three-dimensional rapid mixing

We developed a new passive-type micromixer based on the baker's transformation and realized a fast mixing of a protein solution, which has lower diffusion constant. The baker's transformation is an ideal mixing method, but there is no report on the microfluidic baker's transformation (MBT), since it is required to fabricate the complicated three-dimensional (3D) structure to realize the MBT device. In this note, we successfully fabricate the MBT device by using precision diamond cutting of an oxygen-free copper substrate for the mould fabrication and PDMS replication. The MBT device with 10.4 mm mixing length enables us to achieve complete mixing of a FITC solution (D = 2.6 × 10(-10) m(2) s(-1)) within 51 ms and an IgG solution (D = 4.6 × 10(-11) m(2) s(-1)) within 306 ms. Its mixing speed is 70-fold higher for a FITC solution and 900-fold higher for an IgG solution than the mixing speed by the microchannel without MBT structures. The Péclet number to attain complete mixing in the MBT device is estimated to be 6.9 × 10(4).     

Modification of the glass surface property in PDMS-glass hybrid microfluidic devices

This paper presents a simple method to change the hydrophilic nature of the glass surface in a poly(dimethylsiloxane) (PDMS)-glass hybrid microfluidic device to hydrophobic by an extra-heating step during the fabrication process. Glass substrates bonded to a native or oxygen plasma-treated PDMS chip having microchambers (12.5 mm diameter, 110 μm height) were heated at 200°C for 3 h, and then the hydrophobicity of the glass surfaces on the substrate was evaluated by measuring the contact angle of water. By the extra-heating process, the glass surfaces became hydrophobic, and its contact angle was around 109°, which is nearly the same as native PDMS surfaces. To demonstrate the usefulness of this surface modification method, a PDMS-glass hybrid microfluidic device equipped with microcapillary vent structures for pneumatic manipulation of droplets was fabricated. The feasibility of the microcapillary vent structures on the device with the hydrophobic glass surfaces are confirmed in practical use through leakage tests of the vent structures and liquid handling for the electrophoretic separation of DNA molecules.     

Polydimethylsiloxane-functionalized monolithic silica column for reversed-phase capillary liquid chromatography

A polydimethylsiloxane (PDMS)-modified monolithic silica column was prepared for performing reversed-phase capillary liquid chromatography. The prepared PDMS column has a permeability of 6.4×10(-14) m(2) with a plate height <9.2 μm. Alkylbenzenes and polycyclic aromatic hydrocarbons (PAHs) were well separated with the PDMS stationary phase, which exhibited similar selectivity and separation mechanism to that of octadecyl stationary phase. The hydrophobic interactions between the analytes and the PDMS stationary phase mainly play the roles for the separation of alkylbenzenes and PAHs. The characteristics of the PDMS column for the separation of alkylbenzenes and PAHs demonstrated that it would be a promising alternative to the octadecyl column.