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Abstract For successful treatment of diseases, sufficient therapeutics must be provided to the body. Microneedle applications in therapeutic delivery and analytics sampling are restricted because of various issues, including smaller area for drug loading and analytics sampling. To achieve sufficient drug loading and analytics sampling and improve drug penetration while maintaining painless administration, patch-type microneedle arrays were designed and fabricated using polymer casting from a conical cavity mold. Microcavities were formed on a carbon plate via micromechanical machining. A porous polymer layer was coated on a microneedle patch (MNP). The pores of the porous polymer layer provided space and channels for drug delivery. A pH-sensitive polymer layer was employed to cap the porous polymer layer, which prevented drug leakage during storage and provided a stimulus drug release in response to body pH conditions. The drug can be delivered through holes connected to both sides of the patch. The drug release of the MNP was investigated in vitro and in vivo and showed conceptual proof that these MNs have the potential to enhance treatment protocols for various diseases with the flexibility of coating and therapeutic materials and offer significant scope for further variations and advancement.

The development of microfluidic and nanofluidic devices is gaining remarkable attention due to the emphasis put on miniaturization of conventional energy conversion and storage processes. A microfluidic fuel cell can integrate flow of electrolytes, electrode-electrolyte interactions, and power generation in a microfluidic channel. Such microfluidic fuel cells can be categorized on the basis of electrolytes and catalysts used for power generation. In this work, for the first time, a single microfluidic fuel cell was harnessed by using different fuels like glucose, microbes and formic acid. Herein, multi-walled carbon nanotubes (MWCNT) acted as electrode material, and performance investigations were carried out separately on the same microfluidic device for three different types of fuel cells (formic acid, microbial and enzymatic). The fabricated miniaturized microfluidic device was successfully used to harvest energy in microwatts from formic acid, microbes and glucose, without any metallic catalyst. The developed microfluidic fuel cells can maintain stable open-circuit voltage, which can be used for energizing various low-power portable devices or applications.

In this study, we present an in situ microfluidic system to precisely control highly porous polycaprolactone microspheres as tissue templates for tissue engineering. The porosity of the microspheres was controlled by adjusting the flow rates of the polymer phase and the pore-generating material phase in the dispersed phase. The microfluidic flow-focusing technique was adopted to manufacture porous microspheres using a relatively highly viscous polymer solution, and the device was fabricated by conventional photolithography and PDMS casting. The fabricated in situ microfluidic system was used to precisely control the pore size of monodispersed polycaprolactone microspheres. The porous microspheres with controlled pore sizes were evaluated by culturing HDF cells on the surface of porous microspheres and injection into the subcutaneous tissue of rats. We found that the increased pore size of the microspheres improved the initial proliferation rate of HDF cells after seeding and relieved the inflammatory response after the implantation of porous microspheres in the subcutaneous tissue of rats.

The tip and die for manufacturing multi-lumen catheter tubes should be designed considering the flow velocity of the molten polymer and the deformation of the final extruded tube. In this study, to manufacture non-circular double-lumen tubes for peripherally inserted central catheters (PICCs), three types of tip and die structures are proposed. The velocity field and swelling effect when the circular tip and die (CTD) are applied, which is the commonly used tip and die structure, are analyzed through numerical calculation. To resolve the wall and rib thickness and ovality issues, the ellipse tip and die (ETD) and sub-path tip and die (STD) were proposed. In addition, based on the results of numerical analysis, the tip and die structures were manufactured and used to perform extrusion. Finally, we manufactured tubes that satisfied the target diameter, ovality, wall, and rib thickness using the newly proposed STD.

We developed an integrated PCR system that performs automated sample preparation and fast polymerase chain reaction (PCR) for application in point-of care (POC) testing. This system is assembled from inexpensive 3D-printing parts, off-the-shelf electronics and motors. Molecular detection requires a series of procedures including sample preparation, amplification, and fluorescence intensity analysis. The system can perform automated DNA sample preparation (extraction, separation and purification) in ≤5 min. The variance of the automated sample preparation was clearly lower than that achieved using manual DNA extraction. Fast thermal ramp cycles were generated by a customized thermocycler designed to automatically transport samples between heating and cooling blocks. Despite the large sample volume (50 μL), rapid two-step PCR amplification completed 40 cycles in ≤13.8 min. Variations in fluorescence intensity were measured by analyzing fluorescence images. As proof of concept of this system, we demonstrated the rapid DNA detection of pathogenic bacteria. We also compared the sensitivity of this system with that of a commercial device during the automated extraction and fast PCR of Salmonella bacteria.

In this article, we describe an enzyme-based, membraneless, microfluidic biofuel cell for the continuous determination of glucose using electrochemical power generation as a transducing signal. Enzymes were immobilized on multi-walled carbon nanotube (MWCNT) electrodes placed parallel to the co-laminar flow in a Y-shaped microchannel. The microchannel was produced with polydimethylsiloxane (PDMS) using soft lithography, while the MWCNT electrodes were replicated via a PDMS stencil on indium tin oxide (ITO) glass. Moreover, the electrodes were modified with glucose oxidase and laccase by direct covalent bonding. The device was studied at different MWCNT deposition amounts and electrolyte flow rates to achieve optimum settings. The experimental results demonstrated that glucose could be determined linearly up to a concentration of 4 mM at a sensitivity of 31 mV∙mM−1cm−2.

A soundwave is transmitted by adjacent molecules in the medium, and depending on the type of sound, it exhibits various characteristics such as frequency, sound pressure, etc. If the acoustic wavelength of the soundwave is sufficiently long compared with the size of an acoustic element, physical analysis within the sound element could be simplified regardless of the shape of the acoustic element: this is called “long wavelength approximation”. A Helmholtz resonator, a representative acoustic element which satisfies the “long wavelength theory”, consists of a neck part and a cavity part. The Helmholtz resonators can absorb certain frequencies of sound through resonance. To exhibit attenuation properties at ultrasound range, the Helmholtz resonator should be made into a microscale since Helmholtz resonators should satisfy the “long wavelength approximation”. In this study, Helmholtz resonator inspired acoustic elements were fabricated using MEMS technology, and acoustic attenuation experiments in a water bath were conducted using various shapes and materials. As a result, the fabricated samples showed admirable attenuation properties up to ~13 dB mm−1 at 1 MHz. The results were analyzed to derive the necessary conditions for the fabrication of acoustic elements with acoustic attenuation properties in ultrasound range.

Thermal performance enhancement in microchannel heat sinks has recently become a challenge due to advancements in modern microelectronics, which demand compatibility with heat sinks able to dissipate ever-increasing amounts of heat. Recent advancements in manufacturing techniques, such as additive manufacturing, have made the modification of the microchannel heat sink geometry possible well beyond the conventional rectangular model to improve the cooling capacity of these devices. One such modification in microchannel geometry includes the introduction of secondary flow channels in the walls between adjacent mainstream microchannels. The present study computationally models secondary flow channels in regular trapezoidal and parallel orientations for fluid circulation through the microchannel walls in a heat sink design. The heat sink is made of silicon wafer, and water is used as the circulating fluid in this study. Continuity, momentum, and energy equations are solved for the fluid flow through the regular trapezoidal secondary flow and parallel secondary flow designs in the heat sink with I-type, C-type, and Z-type inlet–outlet configurations. Plots of velocity contours show that I-type geometry creates optimal flow disruption in the heat sink. Therefore, for this design, the pressure drop and base plate temperatures are plotted for a volumetric flow rate range, and corresponding contour plots are obtained. The results are compared with corresponding trends for the conventional rectangular microchannel design, and associated trends are explained. The study suggests that the flow phenomena such as flow impingement onto the microchannel walls and formation of vortices inside the secondary flow passages coupled with an increase in heat transfer area due to secondary flow passages may significantly improve the heat sink performance.

As the market for minimally invasive surgery has grown, the demand for high-precision and high-performance catheters has increased. Catheters for the diagnosis and treatment of cardiovascular or cerebrovascular disease mainly use a braided wire tube with a polymer inner liner and outer jacket to improve the pushability and trackability. The outer jacket should have an accurate inner and outer diameter and while maintaining a wall thickness of 150 µm or less. In this study, we designed and manufactured a tip and die capable of extruding an outer jacket with a wall thickness of 150 µm or less using a medical thermoplastic elastomer for manufacturing 8Fr (2.64 mm diameter) thin-walled tubes. The ovality and inner/outer diameters of the tube were studied according to changes in the screw speed (mass flow rate), puller speed, air pressure applied to the lumen, and distance between the quench and head, which are the main variables of microextrusion processes. The screw speed (mass flow rate), puller speed, and air pressure affected the inner/outer diameter of the tube, with screw speed and puller speed having the largest influence on diameter. The air pressure and distance between quench and head had the greatest influence on ovality. The results show the effect of different processing parameters on the characteristics of the extruded tube, which will help to establish a stable extrusion process for the manufacture of outer jackets for braided catheter shafts.

A closed-loop system imitating the function of pancreatic cells, connected to microneedles (MNs) that automatically “release” insulin in response to the blood glucose (BG) levels would be highly satisfactory for improving the quality of life and health for diabetes patients. This paper describes an easy, fast and simple technique of coating a porous polymer layer on stainless steel (SS) MNs that release insulin in a glucose-responsive fashion. It was fabricated by sealing insulin, sodium bicarbonate (a pH-sensitive element [NaHCO3]) and glucose oxidase (glucose-specific enzymes [GOx]) into the pores of a porous polymer coating. Glucose can passively diffuse into the pores and become oxidized to gluconic acid by GOx, thereby causing a decrease in local pH. The subsequent reaction of protons with NaHCO3 forms carbon dioxide (CO2) which creates pressure inside the pores, thereby rupturing the thin polymer film and releasing the encapsulated insulin. Field emission scanning electron microscopy (FE-SEM) images displayed that upon the exposure of MNs to glucose-free phosphate buffer saline (PBS) with pH 7.4, the pores of the porous MNs were closed, while in MNs exposed to a hyperglycemic glucose level, the pores were opened and the thin film burst. These MNs demonstrated both in vitro (in porcine skin and PBS) and in vivo (in diabetic rats) glucose-mediated insulin release under hyperglycemic conditions with rapid responsiveness. This study validated that the release of insulin from porous MNs was effectively correlated with glucose concentration.

We present a 512-channel geometric droplet-splitting microfluidic device that involves the injection of a premixed emulsion for microsphere production. The presented microfluidic device was fabricated using conventional photolithography and polydimethylsiloxane casting. The fabricated microfluidic device consisted of 512 channels with 256 T-junctions in the last branch. Five hundred and twelve microdroplets with a narrow size distribution were produced from a single liquid droplet. The diameter and size distribution of prepared micro water droplets were 35.29 µm and 8.8% at 10 mL/h, respectively. Moreover, we attempted to prepare biocompatible microspheres for demonstrating the presented approach. The diameter and size distribution of the prepared poly (lactic-co-glycolic acid) microspheres were 6.56 µm and 8.66% at 10 mL/h, respectively. To improve the monodispersity of the microspheres, we designed an additional post array part in the 512-channel geometric droplet-splitting microfluidic device. The monodispersity of the microdroplets prepared with the microfluidic device combined with the post array part exhibited a significant improvement.

We present a simple method to coat microneedles (MNs) uniformly with a porous polymer (PLGA) that can deliver drugs at high rates. Stainless steel (SS) MNs of high mechanical strength were coated with a thin porous polymer layer to enhance their delivery rates. Additionally, to improve the interfacial adhesion between the polymer and MNs, the MN surface was modified by plasma treatment followed by dip coating with polyethyleneimine, a polymer with repeating amine units. The average failure load (the minimum force sufficient for detaching the polymer layer from the surface of SS) recorded for the modified surface coating was 25 N, whereas it was 2.2 N for the non-modified surface. Calcein dye was successfully delivered into porcine skin to a depth of 750 µm by the porous polymer-coated MNs, demonstrating that the developed MNs can pierce skin easily without deformation of MNs; additional skin penetration tests confirmed this finding. For visual comparison, rhodamine B dye was delivered using porous-coated and non-coated MNs in gelatin gel which showed that delivery with porous-coated MNs penetrate deeper when compared with non-coated MNs. Finally, lidocaine and rhodamine B dye were delivered in phosphate-buffered saline (PBS) medium by porous polymer-coated and non-coated MNs. For rhodamine B, drug delivery with the porous-coated MNs was five times higher than that with the non-coated MNs, whereas 25 times more lidocaine was delivered by the porous-coated MNs compared with the non-coated MNs.

This work demonstrates a simple approach for coating a porous polymer layer on stainless-steel (SS) microneedles characterized by a pH-responsive formulation for self-regulated drug delivery. For many drug-delivery applications, the release of therapeutic agents in an acidic microenvironment is desirable. Acid-sensitive polymers and hydrogels were extensively explored, but easily prepared polymeric microcarriers that combine acid sensitivity and biodegradability are rare. Here, we describe a simple and robust method of coating a porous polymer layer on SS microneedles (MNs) that release a model drug (lidocaine) in a pH-responsive fashion. It was constructed by packing the model drug and a pH-sensitive component (sodium bicarbonate) into the pores of the polymer layer. When this acid-sensitive formulation was exposed to the acidic microenvironment, the consequent reaction of protons (H+) with sodium bicarbonate (NaHCO3) yielded CO2. This effect generated pressure inside the pores of the coating and ruptured the thin polymer membrane, thereby releasing the encapsulated drug. Scanning electron micrographs showed that the pH-sensitive porous polymer-coated MNs exposed to phosphate-buffered saline (PBS) at pH 7.4 were characterized by closed pores. However, MNs exposed to PBS at pH 5.5 consisted of open pores and the thin membrane burst. The in vitro studies demonstrated the pH sensitivity of the drug release from porous polymer-coated MNs. Negligible release was observed for MNs in receiving media at pH 7.4. In contrast, significant release occurred when the MNs were exposed to acidic conditions (pH 5.5). Additionally, comparable results were obtained for drug release in vitro in porcine skin and in PBS. This revealed that our developed pH-responsive porous polymer-coated MNs could potentially be used for the controlled release of drug formulations in an acidic environment. Moreover, the stimuli-responsive drug carriers will enable on-demand controlled release profiles that may enhance therapeutic effectiveness and reduce systemic toxicity.

We present a 512-microchannel geometrical passive breakup device for the mass production of microdroplets. The mass production is achieved through the passive breakup of a droplet into two droplets. The microchannel geometry in the microfluidic device was designed and optimized by focusing on stable droplet splitting for microdroplet preparation and minimizing the hydraulic resistance of the microchannel for achieving high throughput; the minimization of hydraulic resistance was achieved by employing analytical approaches. A total of 512 microdroplets could be prepared from a single liquid plug by making the liquid plug pass through nine sequential T-junctions in the microfluidic device, which led to the splitting of droplets. The microfluidic device was fabricated using conventional photolithography and polydimethylsiloxane (PDMS) casting. We estimated the performance of the microfluidic device in terms of the size distribution and production rate of microdroplets. Microdroplets with a diameter of 40.0 ± 2.2 µm were prepared with a narrow size distribution (coefficient of variation (CV) < 5.5%) for flow rates of disperse (Qd) and continuous phase (Qc) of 2 and 3 mL/h, respectively. Microdroplet production rates were measured using a high-speed camera. Furthermore, monodisperse microdroplets were prepared at 42.7 kHz for Qd and Qc of 7 and 15 mL/h, respectively. Finally, the feasibility of the fabricated microfluidic device was verified by using it to prepare biodegradable chitosan microspheres.

With increasing interest in induced pluripotent stem cells (iPSCs) in the field of stem cell research, highly efficient infection of somatic cells with virus factors is gaining importance. This paper presents a method of employing microfluidic devices for dynamic cell culture and virus infection in a microchannel. The closed space in the microchannel provided a better environment for viruses to diffuse and contact cell surfaces to infect cells. The microfluidic devices were fabricated by photolithography and soft lithography. NIH/3T3 fibroblast cells were cultured in the microfluidic device in static and dynamic conditions and compared with the conventional culture method of using Petri dishes. Virus infection was evaluated using an enhanced green fluorescent protein virus as a model. Dynamic culture in the microchannel showed similar growth of cells to that in Petri dish culture, but the virus infection efficiency was four-times higher. The proposed dynamic culture system could be useful in iPSC research by providing efficient virus infection tools.

We present a 1600 parallel microchamber microfluidic device for fast sample array preparation using the immiscibility of two liquids. The trapping efficiency and size of the arrayed sample in the microchambers of a parallel microfluidic device were analyzed at various flow rates. The trapping efficiency of the sample was also inspected according to the position of the microchamber. Samples were successfully arrayed using the device. The trapping efficiency of the sample was 98.69% at 1 mL/h. The trapping efficiency and diameter of the sample decreased as the flow rate increased. Trapping efficiencies also changed according to the position of the microchambers. As the distance of the microchambers from the inlet increased, the sample trapping efficiency decreased. This tendency occurred more clearly at higher flow rates.

Cell membrane receptors and ion channels are essential in many different cellular processes. To analyze the activity of membrane proteins in vesicles and biological cells, we fabricated micro-nano structured chips, enabling the application of electro physiology and fluorescence-based techniques. A SU-8 biochip was developed to simultaneously micromanipulate and investigate optically and electrically individual vesicles in a microfluidic channel. Lipid vesicles were transported, positioned by electrophoretic movement on a micrometer sized aperture, and fused to form a planar suspended membrane, which is suited to study ion channel activity. Aiming to investigate G protein coupled receptor signaling pathways in native-like environment, we developed a method for producing well-Oriented planar cell membrane sheets on silicon films containing nanoaperture arrays. The accessibility of extracellular and cytosolic surfaces was demonstrated by targeting membrane constituents side-specifically with fluorescent markers. Our approach can be applied for studying membrane proteins from a large variety of cells and cellular or ganelles using chip-based screening assays.