Quantification methods comparing in vitro and in vivo percutaneous permeation by microneedles and passive diffusion.

Microneedles (MNs) are needles with a tip diameter ranging from 10 to 100 um and a length ranging up to 1 mm. The first patent for drug delivery device for percutaneous administration filed by Alza corporation dates back to 1976 (Gerstel and Place, 1976), and in between 1989 and 2021 the filed patents for MNs are >4500 [1]. These devices can potential overcome some drawbacks of traditional needles, such as the pain generated during insertion, requirement for trained personnel to manipulate syringes, and difficulty of performing injections in elderly and obese patients. MNs and MN arrays are emerging as a convenient method to deliver compounds and extract blood without causing any pain. A promising application is the use of MNs as alternative solution to topical creams (TC) and transdermal patches (TP) for transdermal drug delivery. The external layer of human skin, the epidermis, offers a major barrier to transdermal drug delivery, thanks to the stratum corneum (SC). Exposed to the external environment, SC ultimately protects the human body from UV light radiation, heat, water loss, bacteria, fungi and viruses, and it is the barrier that controls diffusion rate for almost all compounds. TC and TP applications are limited by the skin permeability to lipophilic compounds and small molecules, and by the slow delivery rate of some compounds. MNs have been around for >35 year now, and it is a general opinion that MNs increase delivery compared to passive diffusion, thanks to the feature of penetrating the SC and reaching the dermis. This review recollects the existing studies that compare MN delivery of drugs with passive diffusion of the same drugs in alive organisms, giving an overview of what are the type of MNs, the chemical delivered and the methods employed to quantify drug delivery into skin and/or in the bloodstream. The final aim is to quantify the enhancement factor of MNs with respect to passive diffusion, and establish a possible standard on how tests can be performed in order to compare different data.

Fabrication and characterization of a microneedle array electrode with flexible backing for biosignal monitoring.

The conventional wet electrode for recording biosignals poses many inconveniences, as it requires an electrolytic gel that dries over time changing its electrical characteristics. The skin typically needs to be abraded when the electrode is applied to record high-quality signals, requiring assistance of trained personnel for the placement of the wet electrode. Alternative electrode designs to overcome these challenges often have difficulties recording small amplitude signals or their fabrication methods are complex and expensive. This research proposes a novel design and a simple fabrication method for a dry microneedle electrode for biosignal monitoring. The electrode can record electroencephalogram and electrocardiogram signals from a human subject without electrolytic gel and it does not require skin preparation such as abrasion, making it suitable for long term measurements as opposed to the wet electrode. When applied to the skin of a human subject with an impact inserter, the electrode has a lower impedance at the skin-electrode interface yielding better signal recording compared to application by hand. The selected electrode materials provides microneedles stiff enough to cross the outmost layer of the skin, while the flexible backing of the electrode has been designed to improve the conformation of the electrode to the rounded shape of the body. The proposed fabrication method for the electrode is based on a simple mold casting process that enables batch production while also reducing the time spent in a cleanroom and the use of expensive machinery.

Determining the factors affecting dynamic insertion of microneedles into skin.

Microneedles are extremely small and minimally-invasive intradermal drug delivery devices that require controlled, accurate, and repeatable insertions into human skin to perform their functions. Due to high variability and elasticity of human skin, dynamic insertion methods are being sought to ensure success in microneedle insertions into the skin passed the tough stratum corneum layer. Dynamic microneedle insertions have not been thoroughly studied to identify and assess the key parameters influencing the skin fracture to date. Here, we have utilized a previously validated artificial mechanical human skin model to identify and evaluate the factors affecting microneedle insertion. It was determined that a microneedle's velocity at impact against the skin played the most crucial role in successfully inserting microneedle devices of different geometrical features (i.e., tip area) and array size (i.e., number of projections). The findings presented herein will facilitate the development of automated microneedle insertion devices that will enable user-friendly and error-free applications of microneedle technologies for medicine delivery.

Precise measurement of intradermal fluid delivery using a low activity technetium-99m pertechnetate tracer.

A method was developed and validated to determine the intradermal (ID) fluid delivery potential of several ID devices, including hollow microneedles. The novel method used water soluble technetium-99 m pertechnetate (99mTcO4-) diluted in normal saline to measure the volume of fluid delivered to and remaining in the skin. The fluid that back-flowed to the skin surface and the fluid left on the device surface were also quantified, thus capturing all fluid volumes deposited during intradermal injections. The technique described in this manuscript was used to assess the injection performance of conventional hypodermic needles and hollow microneedles ex vivo using porcine skin and in vivo with a rat model. Since only a small fraction, 1.1%, of the water-soluble tracer remained bound to the skin when applied topically, the technique can be used to differentiate between injected fluid and backflow. Counting of gamma radiation from 99mTcO4- provided sub-nanoliter resolution for volume measurements, making the proposed method powerful, sensitive, and suitable for the assessments of ID injection devices, particularly for vaccine delivery.

Fluid absorption by skin tissue during intradermal injections through hollow microneedles.

Hollow microneedles are an emerging technology for delivering drugs and therapeutics, such as vaccines and insulin, into the skin. Although the benefits of intradermal drug delivery have been known for decades, our understanding of fluid absorption by skin tissue has been limited due to the difficulties in imaging a highly scattering biological material such as skin. Here, we report the first real-time imaging of skin tissue at the microscale during intradermal injections through hollow microneedles, using optical coherence tomography. We show that skin tissue behaves like a deformable porous medium and absorbs fluid by locally expanding rather than rupturing to form a single fluid filled cavity. We measure the strain distribution in a cross section of the tissue to quantify local tissue deformation, and find that the amount of volumetric expansion of the tissue corresponds closely to the volume of fluid injected. Mechanically restricting tissue expansion limits fluid absorption into the tissue. Our experimental findings can provide insights to optimize the delivery of drugs into skin for different therapeutic applications, and to better model fluid flow into biological tissue.

Effect of substrate conductivity on the evaporation of small sessile droplets.

Here we show the effect of the thermal conductivity of the substrate on the evaporation process of small droplets. We deposited small droplets on the order of 100-500 µm in diameter on four different substrates with different thermal conductivities and surface properties, and we measured the evaporation time. Also, a numerical model that describes this process was developed to include thermal effects inside the droplet and heat transfer from the substrate. Our model considers the entire time of evaporation including the pinned and depinned stages. This model uses a new approach for the contact line behavior. It uses experimental results to define the movement of the contact line as a function of the contact angle.

Integrated hollow microneedle-optofluidic biosensor for therapeutic drug monitoring in sub-nanoliter volumes.

Therapeutic drug monitoring (TDM) typically requires painful blood drawn from patients. We propose a painless and minimally-invasive alternative for TDM using hollow microneedles suitable to extract extremely small volumes (<1 nL) of interstitial fluid to measure drug concentrations. The inner lumen of a microneedle is functionalized to be used as a micro-reactor during sample collection to trap and bind target drug candidates during extraction, without requirements of sample transfer. An optofluidic device is integrated with this microneedle to rapidly quantify drug analytes with high sensitivity using a straightforward absorbance scheme. Vancomycin is currently detected by using volumes ranging between 50-100 µL with a limit of detection (LoD) of 1.35 µM. The proposed microneedle-optofluidic biosensor can detect vancomycin with a sample volume of 0.6 nL and a LoD of <100 nM, validating this painless point of care system with significant potential to reduce healthcare costs and patients suffering.

Design, microfabrication, and characterization of a moulded PDMS/SU-8 inkjet dispenser for a Lab-on-a-Printer platform technology with disposable microfluidic chip.

In this paper, we present a disposable inkjet dispenser platform technology and demonstrate the Lab-on-a-Printer concept, an extension of the ubiquitous Lab-on-a-Chip concept, whereby microfluidic modules are directly integrated into the printhead. The concept is demonstrated here through the integration of an inkjet dispenser and a microfluidic mixer enabling control over droplet composition from a single nozzle in real-time during printing. The inkjet dispenser is based on a modular design platform that enables the low-cost microfluidic component and the more expensive actuation unit to be easily separated, allowing for the optional disposal of the former and reuse of the latter. To limit satellite droplet formation, a hydrophobic-coated and tapered micronozzle was microfabricated and integrated with the fluidics to realize the dispenser. The microfabricated devices generated droplets with diameters ranging from 150-220 µm, depending mainly on the orifice diameter, with printing rates up to 8000 droplets per second. The inkjet dispenser is capable of dispensing materials with a viscosity up to ∼19 mPa s. As a demonstration of the inkjet dispenser function and application, we have printed type I collagen seeded with human liver carcinoma cells (cell line HepG2), to form patterned biological structures.

Compact near-eye display system using a superlens-based microlens array magnifier.

A new type of very compact optical element for a near-eye display (NED) that uses a pair of microlens arrays (MLAs) is presented. The MLA pair works in conjunction to form a magnifier (collimator). The purpose of this is to aid in the accommodation of the eye on a head-up display that is positioned within several centimeters from the eye; the MLA pair collimates the light rays departing from the display thereby generating a virtual image of the display at optical infinity. By using the MLA pair, we are able to make a collimator that retains a thin profile of about 2 mm in thickness with a system focal length of about 7 mm.

Slip of Spreading Viscoplastic Droplets.

The spreading of axisymmetric viscoplastic droplets extruded slowly on glass surfaces is studied experimentally using shadowgraphy and swept-field confocal microscopy. The microscopy furnishes vertical profiles of the radial velocity using particle image velocimetry (PIV) with neutrally buoyant tracers seeded in the fluid. Experiments were conducted for two complex fluids: aqueous solutions of Carbopol and xanthan gum. On untreated glass surfaces, PIV demonstrates that both fluids experience a significant amount of effective slip. The experiments were repeated on glass that had been treated to feature positive surface charges, thereby promoting adhesion between the negatively charged polymeric constituents of the fluids and the glass surface. The Carbopol and xanthan gum droplets spread more slowly on the treated surface and to a smaller radial distance. PIV demonstrated that this reduced spreading was associated with a substantial reduction in slip. For Carbopol, the effective slip could be eliminated entirely to within the precision of the PIV measurements; the reduction in slip was less effective for xanthan gum, with a weak slip velocity remaining noticeable.

A microneedle-based method for the characterization of diffusion in skin tissue using doxorubicin as a model drug.

Hollow microneedles can overcome the stratum corneum (SC) barrier and deposit a compound directly into the viable epidermis or the dermis, unlike adhesive patches that rely on drug diffusion across the SC. The traditional one-dimensional methods used to study the diffusivity of drugs across the skin layers are not very accurate for hollow microneedles, since the ejection of compounds out of microneedle lumens resembles a point-source spreading in all directions and is highly dependent on injection depth. This paper presents a technique that is useful for studying drug injection using hollow microneedles at various depths below the SC. This technique uses confocal microscopy to image the distribution of a fluorescent compound in the skin after injection. The fluorescence distribution in the skin is observed over time and applied to a spherical Gaussian diffusion model for limited source diffusion to determine the diffusion coefficient of the compound in the skin. Applied to freshly excised pig skin, the diffusion coefficient for the anti-cancer drug doxorubicin was measured as 4.61 × 10(-9) cm(2)/s, while the diffusion coefficient in previously refrigerated or frozen pig skin was 1.31 × 10(-8) cm(2)/s and 4.21 × 10(-8) cm(2)/s, respectively. Our data suggests that skin storage conditions can substantially alter the diffusion of drugs. The use of refrigerated and, even more so, previously frozen skin should be avoided for quantitative transdermal drug delivery studies.

Paper as a platform for sensing applications and other devices: a review.

Paper is a ubiquitous material that has various applications in day to day life. A sheet of paper is produced by pressing moist wood cellulose fibers together. Paper offers unique properties: paper allows passive liquid transport, it is compatible with many chemical and biochemical moieties, it exhibits piezoelectricity, and it is biodegradable. Hence, paper is an attractive low-cost functional material for sensing devices. In recent years, researchers in the field of science and engineering have witnessed an exponential growth in the number of research contributions that focus on the development of cost-effective and scalable fabrication methods and new applications of paper-based devices. In this review article, we highlight recent advances in the development of paper-based sensing devices in the areas of electronics, energy storage, strain sensing, microfluidic devices, and biosensing, including piezoelectric paper. Additionally, this review includes current limitations of paper-based sensing devices and points out issues that have limited the commercialization of some of the paper-based sensing devices.

Controlled spreading of thermo-responsive droplets.

A novel methodology for controlling the spreading of droplets impacting a substrate is presented. The working fluid is a thermo-responsive polymer solution that undergoes a sol-gel transition above a specific temperature. It is shown that the maximum diameter of a droplet at equilibrium can be controlled through the substrate temperature of the substrate and the polymer concentration.

Piezoelectric paper fabricated via nanostructured barium titanate functionalization of wood cellulose fibers.

We have successfully developed hybrid piezoelectric paper through fiber functionalization that involves anchoring nanostructured BaTiO3 into a stable matrix with wood cellulose fibers prior to the process of making paper sheets. This is realized by alternating immersion of wood fibers in a solution of poly(diallyldimethylammonium chloride) PDDA (+), followed by poly(sodium 4-styrenesulfonate) PSS (-), and once again in PDDA (+), resulting in the creation of a positively charged surface on the wood fibers. The treated wood fibers are then immersed in a BaTiO3 suspension, resulting in the attachment of BaTiO3 nanoparticles to the wood fibers due to a strong electrostatic interaction. Zeta potential measurements, X-ray diffraction, and microscopic and spectroscopic analysis imply successful functionalization of wood fibers with BaTiO3 nanoparticles without altering the hydrogen bonding and crystal structure of the wood fibers. The paper has the largest piezoelectric coefficient, d33 = 4.8 ± 0.4 pC N(-1), at the highest nanoparticle loading of 48 wt % BaTiO3. This newly developed piezoelectric hybrid paper is promising as a low-cost substrate to build sensing devices.

Modeling and simulation of linear and nonlinear MEMS scale electromagnetic energy harvesters for random vibration environments.

The simulation results for electromagnetic energy harvesters (EMEHs) under broad band stationary Gaussian random excitations indicate the importance of both a high transformation factor and a high mechanical quality factor to achieve favourable mean power, mean square load voltage, and output spectral density. The optimum load is different for random vibrations and for sinusoidal vibration. Reducing the total damping ratio under band-limited random excitation yields a higher mean square load voltage. Reduced bandwidth resulting from decreased mechanical damping can be compensated by increasing the electrical damping (transformation factor) leading to a higher mean square load voltage and power. Nonlinear EMEHs with a Duffing spring and with linear plus cubic damping are modeled using the method of statistical linearization. These nonlinear EMEHs exhibit approximately linear behaviour under low levels of broadband stationary Gaussian random vibration; however, at higher levels of such excitation the central (resonant) frequency of the spectral density of the output voltage shifts due to the increased nonlinear stiffness and the bandwidth broadens slightly. Nonlinear EMEHs exhibit lower maximum output voltage and central frequency of the spectral density with nonlinear damping compared to linear damping. Stronger nonlinear damping yields broader bandwidths at stable resonant frequency.

Low cost integration of 3D-electrode structures into microfluidic devices by replica molding.

We demonstrate a new replica molding method for integrating 3D-composite electrodes into microfluidic devices made from polydimethylsiloxane (PDMS) at low cost. Our process does not require work in a cleanroom, expensive materials, or expensive equipment once a micro mold has been fabricated using standard multilayer SU-8 photolithography. Different device geometries have been fabricated to demonstrate the capabilities and limitations of the method. The electrical properties of the composite electrode material are characterized. Furthermore, a device for concentrating particles via AC-dielectrophoresis is presented as an example for a potential application of the fabrication process.

Substrate-free fabrication of self-supporting ZnO nanowire arrays.

Thin films composed of self-supporting ZnO nanowire arrays are fabricated via a hydrothermal approach without the presence of any substrates. The films can be transferred and bonded to an arbitrary substrate for device applications. As a demonstration, a piezoelectric converter is made which is able to generate electric charge under compressive forces.

Flow manipulation and cell immobilization for biochemical applications using thermally responsive fluids.

A flow redirection and single cell immobilization method in a microfluidic chip is presented. Microheaters generated localized heating and induced poly(N-isopropylacrylamide) phase transition, creating a hydrogel that blocked a channel or immobilized a single cell. The heaters were activated in sets to redirect flow and exchange the fluid in which an immobilized cell was immersed. A yeast cell was immobilized in hydrogel and a 4',6-diamidino-2-phenylindole (DAPI) fluorescent stain was introduced using flow redirection. DAPI diffused through the hydrogel and fluorescently labelled the yeast DNA, demonstrating in situ single cell biochemistry by means of immobilization and fluid exchange.