Stainless Steel Microneedles Research Articles

From microchips to microneedles: semiconductor shear testers as a universal solution for transverse load analysis of microneedle mechanical performance

Abstract Microneedles are a promising technology for pain-free and efficient pharmaceutical delivery. However, their clinical translation is currently limited by the absence of standardized testing methods for critical quality attributes (CQAs), such as mechanical robustness, which are essential for demonstrating safety and efficacy during regulatory review. A key aspect of mechanical robustness is transverse load capacity, which is currently assessed using diverse, non-standardized methods, which have limited capability to measure transverse failure forces at different heights along a microneedle. This is critical for understanding mechanics of potential failure modes during insertion after skin penetration. In this work we utilize a wire bond shear tester, a piece of test equipment widely used in the semiconductor industry, to measure the transverse load capacities of various microneedle designs. This approach is compatible with diverse microneedle types, geometries, and materials, and offers high-throughput and automated testing capabilities with high precision. We measure transverse failure loads with micron-scale control over the test height and have established comprehensive profiles of mechanical robustness along the length of different microneedle designs, which is a capability not previously demonstrated in literature for polymeric and metal microneedles. Transverse failure forces were 10±0.3 gf to 128±12 gf for wire bonded gold and silver microneedles, 11±0.7 gf to 480±69 gf for conical and pyramidal polymeric microneedles, and 206±80 gf to 381±1 gf for 3D printed conical stainless steel microneedles. Additionally, we present standardized definitions for microneedle structural failure modes resulting from transverse loads, which can facilitate root cause failure analysis and defect detection during design and manufacturing, and aid in risk assessment of microneedle products. This work establishes a standardized approach to evaluating a significant CQA of microneedle products, which is a critical step towards expediting their clinical adoption.

Nanoporous Carbon Materials as Solid Contacts for Microneedle Ion-Selective Sensors.

Continuous sensing of biomarkers, such as potassium ions or pH, in wearable patches requires miniaturization of ion-selective sensor electrodes. Such miniaturization can be achieved by using nanostructured carbon materials as solid contacts in microneedle-based ion-selective and reference electrodes. Here we compare three carbon materials as solid contacts: colloid-imprinted mesoporous (CIM) carbon microparticles with ∼24-28 nm mesopores, mesoporous carbon nanospheres with 3-9 nm mesopores, and Super P carbon black nanoparticles without internal porosity but with textural mesoporosity in particle aggregates. We compare the effects of carbon architecture and composition on specific capacitance of the material, on the ability to incorporate ion-selective membrane components in the pores, and on sensor performance. Functioning K+ and H+ ion-selective electrodes and reference electrodes were obtained with gold-coated stainless-steel microneedles using all three types of carbon. The sensors gave near-Nernstian responses in clinically relevant concentration ranges, were free of potentially detrimental water layers, and showed no response to O2. They all exhibited sufficiently low long-term potential drift values to permit calibration-free, continuous operation for close to 1 day. In spite of the different specific capacitances and pore architecture of the three types of carbon, no significant difference in potential stability for K+ ion sensing was observed between electrodes that used each material. In the observed drift values, factors other than the carbon solid contact are likely to play a role, too. However, for pH sensing, electrodes with CIM as a carbon solid contact, which had the highest specific capacitance and best access to the pores, exhibited better long-term stability than electrodes with the other carbon materials.

Impact of Formulation and Microneedle Length on Transdermal Metronidazole Permeation through Microneedle-Treated Skin.

This study aimed to determine the impact of formulation (gel vs cream) and microneedle characteristics (length, number) on permeation of metronidazole through excised microneedle-treated skin. The long-term goal is to apply these results towards a pharmacokinetic study in human subjects with diverse skin types, using in vitro flux data to determine dosing conditions and ultimately establish in vitro-in vivo correlations. Metronidazole release from 0.75% gel and cream was quantified with flow-through diffusion cells, using a cellulose membrane. Excised porcine skin was treated with stainless steel microneedles (500 or 800μm length), to create 50 or 100 micropores. Metronidazole gel or cream was applied to microneedle-treated skin and replaced every 48h for up to 7days. Metronidazole permeation was quantified using HPLC. Intact skin (no microneedle treatment) served as controls. Metronidazole release was faster from the gel vs cream. At 7days there was no difference between gel vs cream in total metronidazole permeated through intact skin. For both formulations, metronidazole permeation was significantly higher (vs intact skin) following microneedle application, regardless of microneedle length or micropore number. Increasing microneedle length and micropore number enhanced MTZ permeation multiple fold for both gel and cream. The greatest enhancement in total permeation for both formulations was achieved with the 800μm MN, 100 micropore condition. Formulation and microneedle conditions both impacted metronidazole permeation. These data will be used to estimate in vivo serum concentrations after applying metronidazole to microneedle-treated skin in humans.

Development of a Self-Powered Microneedle Based Wearable Electrochemical Sensor for Glucose Monitoring

Diabetes is increasingly being recognized as a worldwide public health concern owing to the affected rate of the patients in the past years. One of the major barriers to the disease control is the lack of sensitive and reliable point-of-care device that can provide quantitative diagnosis and monitoring. The wearable sensing technology has the potential of revolutionizing the precision medicine and personalized healthcare system. Within the emerging class of wearables, the microneedle-based sensors play a key role in combining the advantages of monitoring the analytes in interstitial fluid (ISF) and minimally invasive skin pricking. However, such devices require appropriate power sources to realize their full capacity, and the increasing power costs, global warming, and environmental pollution are certain aspects that needs to be pondered upon. Researches are dedicated on power generators with focus on wearable energy harvesters to address the issue of power supply. Thermoelectric generators (TEGs) have the ability to generate power by transforming thermal energy to electrical power output. Herein, we have developed a microneedle based enzymatic, electrochemical glucose sensing system powered by TEG utilizing the body heat. 1 mm stainless steel microneedles were sputtered with gold and platinum, and further coated with graphene paste, glucose oxidase, poly-hydroxyethyl methacrylate, and nafion. The fabricated device exhibited a good sensitivity, and a wide linear range. According to the World Health Organization (WHO), the normal glucose level in human body are between 4.0 mM to 5.6 mM, and our device has shown a concentration dependent output current signal from 4.0 mM to 24.0 mM. The device has also exhibited excellent detection results in real-sample (artificial ISF) in vitro study as well as in vivo analysis performed in 12 – 15 weeks SD rats. The device is completely self-powered where the TEG derives power from the temperature gradient between the body heat and the exposed environment. The novelty of this work lies in integrating the microneedle-based sensing device with the TEG as the power source. The results indicate a promising self-powered sensor with the renewable and sustainable source of power ensuring continuous operation.

Development of Wearable Microneedle-Based Platform for Real-Time Biomarkers Sensing

The wearable device technology plays a huge role in the healthcare sector owing to the aging global population and increased acquisition of the internet of things (IoT). Further, the Coronavirus Disease-2019 (COVID-19) pandemic has accelerated the emergence of wearable medical devices in the market. The patients with chronic diseases are more focused on tracking single or multiple nutrients and biomarkers in the body. Diabetes is a classic example of chronic disease where the patients need to monitor their blood glucose level for a long time. In addition, diabetic patients also face electrolyte imbalance which gives rise to several other diseases. There is an immense urgency to develop a sensing platform that can detect the essential ions as well as biomarkers from the interstitial fluid (ISF) as it contains valuable information about the physiological status of a person. According to Centers for Disease Control and Prevention (CDC), imbalance of sodium concentration in the body may lead to stroke, hypertension, and epilepsy; for potassium: arrhythmia, chronic kidney disease (CKD), and dizziness; for calcium: depression, osteoporosis, and other bone-related disease; for pH of body fluid: urinary tract infection, respiratory acidosis, and sleep apnea. Within this advent of wearables, microneedle (MN)-based transdermal sensors are well positioned to play a key role in combining the significant benefits of dermal interstitial fluid (ISF) as a source of clinical indicators and minimally invasive skin puncturing to allow the collection of real-time diagnostic data. In this context, we have developed a MNs based versatile platform for the transdermal amperometric detection of glucose and different clinically relevant biomarkers such as K+, Na+, Ca2+ in the body fluid in a robust, reliable, and cost-effective way. Here, stainless steel microneedle (SS-MN) is used as an ideal candidate for multiplex sensing due to its great chemical stability as well as the rigidity for accurate and painless puncture. The device is fabricated with ion selective electrode (ISM) coating on each needle for their corresponding electrolyte and enzyme for glucose detection. In vitro experiments performed in artificial ISF samples yielded excellent sensitivity and a good linear response. The sensor is successfully applied for in vivo detection of glucose and these ions in SD rats for validating their feasibility as a real-time sensing device. Overall, this developed concept comprises of significant progress in the sensing of glucose and other ions in relation to an electrolyte imbalance in the humans that holds relevance in controlling several diseases.

Microneedle Enabled Electrochemical Aptamer-Based Sensing: Real Time Measurements Using Stainless Steel Microneedles

Electrochemical aptamer-based (EAB) sensors are among the only generalizable sensing platforms that resist fouling enough to function directly in bodily fluids and in situ in the living body. Already, these sensors have enabled the real-time measurement of a range of small molecule targets in vivo, including pharmaceuticals and drugs of abuse. EAB sensors consist of an electrode-attached, redox reporter-labeled aptamer that binds to its target species. Target binding causes a shift in electron-transfer rate between the redox reporter and electrode surface, easily detected by a range of electrochemical techniques. Here, we explore the application of EAB sensors to minimally-invasive molecular monitoring. Specifically, we adapt the platform to a microneedle device format. Microneedles can provide direct access to the skin’s interstitial space – a bodily compartment that holds valuable information ranging from drug distribution and immune status. And because microneedles can penetrate into the top layers of the skin with minimal nerve endings, they can avoid eliciting notable pain responses.In this work, we demonstrate the substantial miniaturization of the sensing platform into electrodes thinner than a human hair, and then integrate them with ultra-fine, hollow microneedles. To ensure needle sterilizability and sharpness while avoiding complex fabrication, we utilize commercial off the shelf stainless steel microneedles. Using an EAB sensor responding to the high-toxicity small molecule drug, vancomycin, as a model system, we achieve quantitative measurements directly in body temperature, undiluted whole blood. Building on this milestone, we explore the application of the sensors when inserted into porcine skin. In porcine skin (a common proxy for human skin), we observe facile microneedle penetration and stable electrochemical signaling. Because of the individual addressability of the sensing electrodes and the generalizability of the aptamer platform, this technology is capable of multiplexed, simultaneous detection of many different molecular targets. Thus, microneedle-enabled aptamer-based sensors offer a promising route forward for non-invasive physiological monitoring – applicable to therapeutic drug monitoring, pain-free biomarker detection, and disease management.

Microneedle electrochemical aptamer-based sensing: Real-time small molecule measurements using sensor-embedded, commercially-available stainless steel microneedles

Microneedle sensors could enable minimally-invasive, continuous molecular monitoring – informing on disease status and treatment in real-time. Wearable sensors for pharmaceuticals, for example, would create opportunities for treatments personalized to individual pharmacokinetics. Here, we demonstrate a commercial-off-the-shelf (COTS) approach for microneedle sensing using an electrochemical aptamer-based sensor that detects the high-toxicity antibiotic, vancomycin. Wearable monitoring of vancomycin could improve patient care by allowing targeted drug dosing within its narrow clinical window of safety and efficacy. To produce sensors, we miniaturize the electrochemical aptamer-based sensors to a microelectrode format, and embed them within stainless steel microneedles (sourced from commercial insulin pen needles). The microneedle sensors achieve quantitative measurements in body-temperature undiluted blood. Further, the sensors effectively maintain electrochemical signal within porcine skin. This COTS approach requires no cleanroom fabrication or specialized equipment, and produces individually-addressable, sterilizable microneedle sensors capable of easily penetrating the skin. In the future, this approach could be adapted for multiplexed detection, enabling real-time monitoring of a range of biomarkers.

A Hybrid Stainless-Steel SPME Microneedle Electrode Sensor for Dual Electrochemical and GC-MS Analysis.

A mechanically robust in-tube stainless steel microneedle solid phase microextraction (SPME) platform for dual electrochemical and chromatographic detection has been demonstrated. The SPME microneedle was fabricated by layer-by-layer (LbL) in-tube coating, consisting of carbon nanotube (CNT)/cellulose nanocrystal (CNC) film layered with an electrically conductive polyaniline (PANI) hydrogel layer (PANI@CNT/CNC SPME microneedle (MN)). The PANI@CNT/CNC SPME MN showed effective analysis of caffeine by GC-MS with an LOD of 26 mg/L and excellent precision across the dynamic range. Additionally, the PANI@CNT/CNC SPME MN demonstrated a 67% increase in sensitivity compared to a commercial SPME fiber, while being highly robust for repeated use without loss in performance. For electrochemical detection, the PANI@CNT/CNC SPME MN showed excellent performance for the detection of 3-caffeoylquinic acid (3-CQA). The dynamic range and limits of detection (LOD) for 3-CQA analysis were 75-448 mg/L and 11 mg/L, respectively. The PANI@CNT/CNC SPME MN was demonstrated to accurately determine the caffeine content and 3-CQA in tea samples and dark roast coffee, respectively. The PANI@CNT/CNC SPME MN was used for semiquantitative antioxidant determination and composition analysis in kiwi fruit using electrochemistry and SPME-coupled GC-MS, respectively.

Intradermal delivery of a quadrivalent cell-based seasonal influenza vaccine using an adjuvanted skin patch vaccination platform.

All seasonal influenza vaccines for 2021-2022 in the US were quadrivalent and the market continues to be dominated by intramuscular delivery of non-adjuvanted, virion-derived antigens grown in chicken eggs. Up to four new egg-adapted production influenza vaccine strains must be generated each year. The introduction in 2012 of Flucelvax®, which is grown in mammalian suspension cell culture and uses vaccine production strains without adaptive mutations for efficient growth in eggs, represented a major advance in vaccine production technology. Here we demonstrate that Flucelvax can be reformulated and combined with a liposomal adjuvant containing QS-21 (Verndari Adjuvant System 1.1, VAS1.1) or QS-21 and 3D-PHAD (VAS1.2) for intradermal administration using a painless skin patch, VaxiPatch™. VAS1.2 is similar to AS01B, the adjuvant system used in Shingrix® and Mosquirix™. We show that Flucelvax, when reformulated and concentrated using tangential flow filtration (TFF), maintains hemagglutination and single radial immunodiffusion (SRID) potency. Loading the reformulated Flucelvax material onto VaxiPatch arrays conferred high levels of resistance to heat stress and room temperature stability. TFF enriched vaccine antigens were combined with VAS1.1 or VAS1.2 and dispensed in 10nL drops into the pockets of 36 (total 360 nL) stainless steel microneedles arranged in a microarray 1.2cm in diameter. Using VaxiPatch delivery of 2µg of antigen, we demonstrated intramusuclar-comparable IgG and hemagglutination inhibition (HAI) immune responses in Sprague Dawley® rats. With addition of VAS1.2, antigen-specific IgG titers were increased as much as 68-fold (47-fold for VAS1.1) with improvements in seroconversion for three of four strains (all four were improved by VAS1.1). TFF-reformulated antigens combined with VAS1.1 or VAS1.2 and delivered by VaxiPatch showed only minor skin reactogenicity after 1h and no skin reactogenicity after 24h. These data indicate that VaxiPatch and the VAS system have the potential to be transformative for vaccine delivery.

A Multipurpose and Multilayered Microneedle Sensor for Redox Potential Monitoring in Diverse Food Analysis.

This work presents a multipurpose and multilayered stainless steel microneedle sensor for the in situ redox potential monitoring in food and drink samples, termed MN redox sensor. The MN redox sensor was fabricated by layer-by-layer (LbL) approach. The in-tube multilayer coating comprised carbon nanotubes (CNTs)/cellulose nanocrystals (CNCs) as the first layer, polyaniline (PANI) as the second layer, and the ferrocyanide redox couple as the third layer. Using cyclic voltammetry (CV) as a transduction method, the MN redox sensor showed facile electron transfer for probing both electrical capacitance and redox potential, useful for both analyte specific and bulk quantification of redox species in various food and drink samples. The bulk redox species were quantified based on the anodic/cathodic redox peak shifts (Ea/Ec) on the voltammograms resulting from the presence of redox-active species. The MN redox sensor was applied to detect selected redox species including ascorbic acid, H2O2, and putrescine, with capacitive limits of detection (LOD) of 49.9, 17.8, and 263 ng/mL for each species, respectively. For the bulk determination of redox species, the MN redox sensor displayed LOD of 5.27 × 103, 55.4, and 25.8 ng/mL in ascorbic acid, H2O2, and putrescine equivalents, respectively. The sensor exhibited reproducibility of ~ 1.8% relative standard deviation (%RSD). The MN redox sensor was successfully employed for the detection of fish spoilage and antioxidant quantification in king mushroom and brewed coffee samples, thereby justifying its potential for food quality and food safety applications. Lastly, the portability, reusability, rapid sampling time, and capability of in situ analysis of food and drink samples makes it amenable for real-time sensing applications.

Stainless steel electrochemical capacitive microneedle sensors for multiplexed simultaneous measurement of pH, nitrates, and phosphates.

Concerns for agri-food safety and environmental management require development of simple to use and cost- and time-effective multiplex sensors for point-of-need (PON) chemical analytics by public end-user. Simultaneous detection of nitrates, phosphates, and pH is of importance in soil and water analysis, agriculture, and food quality assessment. This article demonstrates a suite of stainless steel microneedle electrochemical sensors for multiplexed measurement of pH, nitrate, and phosphate using faradaic capacitance derived from cyclic voltammetry as the mode of detection. The multi-target microneedle sensors were fabricated by layer-by-layer (LbL) assembly in a stainless steel hypodermic microneedle substrate. For nitrate sensing, the stainless steel was coated with carbon nanotube/cellulose nanocrystal (CNT)/CNC) decorated with silver nanoparticles (Ag). For pH measurement, the polyaniline (pANI) was coated onto the CNT/CNC@Ag film, while for phosphate detection, the CNT/CNC/Ag @pANI microneedle was further decorated with ammonium molybdenum tetrahydrate (AMT). The microelectrode platforms were characterized by FTIR, Raman, and microscopic techniques. The nitrate- and phosphate-based microneedle electrochemical sensors had excellent selectivity and sensitivity, with a determined limit of detection (LOD) of 0.008mM and 0.007mM, respectively. The pH microneedle sensor was responsive to pH in the linear range of 3-10. The three microneedle sensors yielded repeatable results, with a precision ranging from 4.0 to 7.5% RSD over the concentration ranges tested. The inexpensive (~ 1 $ CAD) microneedle sensors were successfully verified for use in quantification of nitrate, pH, and phosphate in brewed black coffee as a real sample. As such, the microneedle sensors are economical devices and show great promise as robust platforms for PON precision chemical analytics.

Continuous Lactate Monitoring System Based on Percutaneous Microneedle Array.

Lactate measurement is important in the fields of sports and medicine. Lactate accumulation can seriously affect an athlete’s performance. The most common problem caused by lactate accumulation in athletes is muscle soreness due to excessive exercise. Moreover, from a medical viewpoint, lactate is one of the main prognostic factors of sepsis. Currently, blood sampling is the most common approach to lactate measurement for lactate sensing, and continuous measurement is not available. In this study, a low-cost continuous lactate monitoring system (CLMS) is developed based on a percutaneous microneedle array that uses a three-electrode lactate sensor. The working electrode has an area of 10 mm × 6 mm, including a 3 × 3 array of stainless-steel microneedles. The length, width, and thickness of each needle are 1 mm, 0.44 mm, and 0.03 mm, respectively. The working electrode is then plated with gold, polyaniline, lactate enzyme, Nafion, and Poly(2-hydroxyethyl methacrylate) (poly HEMA). The reference electrode is a 2 × 1 array covered with AgCl, and the counter electrode is a 2 × 1 array plated with gold. The sensor is incorporated into the CLMS and connected to a smartphone application and the cloud. The CLMS was tested on 40 human subjects who rode indoor bicycles, starting at 100 W and increasing in steps of 25 W at intervals of 5 min until exhaustion. The data acquired from the app connected to the CLMS were analyzed to determine the subjects’ lactate response to exercise and the feasibility of assessing exercise performance and training exercise intensity by using the proposed system.

Modified stainless steel microneedle electrode for polyphenolics detection.

This work outlines a simple fabricated microneedle electrode for sensitive and real sample monitoring of plant polyphenolics. The electrode was fabricated by layer-by-layer assembly (LBL) with nanocomposite of carbon nanotubes (CNT) and cellulose nanocrystals (CNC) as the first layer, followed by polyaniline (PANI), and finally, the 3-(glycidyloxypropyl)trimethoxysilane (GOPS) layer as the binding agent. The microneedle electrodes were characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS), Fourier transform infrared (FTIR) spectroscopy, and Raman spectroscopy. The developed microneedle electrodes were successfully applied for the capacitive detection of gallic acid (GA) and chlorogenic acid (CA) as polyphenol model compounds. The microneedle electrode was also used to quantify polyphenols in orange juice. The electrochemical capacitance responses were linearly proportional to the concentrations of GA and CA in the range of 0.1-87.23μg/mL for GA and 0.1-78.01μg/mL for CA. The calculated detection limits (LOD) for GA and CA were found to be 0.29 ± 0.2μg/mL and 0.34 ± 0.2μg/mL respectively. As minimally invasive technology, microneedle electrodes were found to be promising for successful in situ screening of antioxidants in different fruit matrices. The microneedle electrodes were also applied to the depth profiling of antioxidant content in fruit samples. Graphical abstract.

VaxiPatch™, a novel vaccination system comprised of subunit antigens, adjuvants and microneedle skin delivery: An application to influenza B/Colorado/06/2017

This work introduces VaxiPatch, a novel vaccination system comprised of subunit glycoprotein vaccine antigens, adjuvants and dermal delivery. For this study, rHA of influenza virus B/Colorado/06/2017 was incorporated into synthetic virosomes, and adjuvant liposomes were formed with QS-21 from Saponaria quillaja, with or without the synthetic TLR4 agonist 3D - (6-acyl) PHAD. These components were concentrated and co-formulated into trehalose with dye. Dermal delivery was achieved using an economical 37-point stainless steel microneedle array, designed for automated fill/finish by microfluidic dispensers used for mass production of immunodiagnostics. Vaccine and adjuvant are deposited to form a sugar glass in a pocket on the side of each of the tips, allowing skin penetration to be performed directly by the rigid steel structure. In this study, Sprague Dawley rats (n = 6 per group) were vaccinated by VaxiPatches containing 0.3 µg of rHA, 0.5 µg QS-21 and 0.2 µg 3D - (6-acyl) PHAD and dye, resulting in antigen-specific IgG titers 100-fold higher than 4.5 µg of FluBlok (p = 0.001) delivered intramuscularly. Similarly, hemagglutination inhibition titers in these animals were 14-fold higher than FluBlok controls (p = 0.01). Non-adjuvanted VaxiPatches were also compared with rHA virosomes injected intramuscularly. Accelerated shelf life studies further suggest that formulated virosomal antigens retain activity for at least two months at 60° C. Further, co-formulation of a dye could provide a visible verification of delivery based on the temporary pattern on the skin. A room-temperature-stable vaccination kit such as VaxiPatch has the potential to increase vaccine use and compliance globally.

Electrochemical modeling and evaluation for textile electrodes to skin

BackgroundWith the development of wearable health-monitoring technologies, a variety of textile electrodes have been produced and applied by researchers. However, there are no universal and effective methods even testing platforms for evaluating the skin–electrode electrochemical interface for textile electrodes because different human bodies have different skin characteristics.MethodsAn electrochemical modeling and evaluation for textile electrodes to skin was proposed, and two electrochemical evaluation platforms (EEP) were set up based on two simulated skin models (SSM). First, skin–electrode electrochemical interface (SEEI) models for traditional wet electrodes and textile electrodes were analyzed. Based on the SEEI models and YY/T 0196-2005 (Chinese YY/T pharmaceutical industry standard for disposable ECG electrode), three skin–electrode electrochemical characteristics (SEEC), including skin–electrode static impedance (SESI), skin–electrode alternating current impedance (SEAI), and skin–electrode polarization voltage (SEPV), were proposed. Then, three electrochemical evaluation methods for textile electrodes to skin were proposed and analyzed, which were the correlation between SEEC and skin–electrode contact pressure (SECP), skin–electrode relative movement (SERM), and conduction loss of active signals (CLAS). Finally, an electrochemical evaluation platform was set up based on an active simulated skin model (ASSM) and passive simulated skin model (PSSM).Results9 feature parameters based on the passive electrochemical evaluation platform (PEEP) and 11 feature parameters based on the active electrochemical evaluation platform (AEEP) were obtained for evaluating textile electrodes. And four kinds of textile electrode characteristics including SEEC, SECP, SERM, and CLAS were quantitatively measured based on the electrochemical evaluation platform, and the testing accuracy and range for these characteristics were measured separately. Finally, correlation between SEEC and SECP for 10 kinds of textile electrode samples was studied, and 14 electrochemical characteristics and four skin–electrode contact pressure characteristics were extracted. Experimental results showed that significant correlations were found between six SEEC characteristics and SECP characteristics, and the correlation coefficient between ACI_3 and USECP was the highest. And the polarization voltages of most dry electrode samples showed a downward trend with the increase of contact pressure.ConclusionsThe electrochemical evaluation platform yielded effective experimental data and could provide strong support for the evaluation and application of textile electrodes, which was also effective in evaluating other bioelectric electrodes such as 3M electrode, stainless steel electrode, dry electrode and microneedle electrode.

Smart Microneedles with Porous Polymer Coatings for pH-Responsive Drug Delivery.

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.

A micro-needle induced strategy for preparation of monodisperse liquid metal droplets in glass capillary microfluidics

Monodisperse micro-sized liquid metal droplets have received considerable attention for developing flexible electronics, microfluidics actuators and reconfigurable devices. Herein we report an innovative and efficient strategy for large-scale preparation of Galinstan liquid metal microdroplets with controllable sizes using a micro-needle induced glass capillary microfluidic device. By inserting a stainless steel micro-needle into the inner liquid metal phase in the glass capillary, the hydrodynamic instability of the liquid metal stream is significantly suppressed to guarantee steady fluid flow before the liquid metal is pinched off by the outer phase flow, giving rise to a stable generation of monodisperse liquid metal microdroplets. The microdroplet size dependence on the flow ratio of the continuous and dispersed-phase is investigated experimentally. A theoretical framework based on the Plateau–Rayleigh instability is proposed to explain the advantage of the micro-needle induced strategy. This strategy has great potential for the generation of high interfacial tension liquid metal emulsions.

The Influence of Microneedles on the Percutaneous Penetration of Selected Antihypertensive Agents: Diltiazem Hydrochloride and Perindopril Erbumine.

Background: It is well documented in the scientific literature that high blood pressure can lead to cardiovascular disease. Untreated hypertension has clinical consequences such as coronary artery dis-ease, stroke or kidney failure. Diltiazem hydrochloride (DH), a calcium-channel blocker, and perindopril erbumine (PE), an inhibitor of the angiotensin converting enzyme are used for the management of hyper-tension.Objective: This project will examine the effect of microneedle rollers on the transport of DH and PE across pig ear skin. The use of the transcutaneous route of administration reduces and in sometimes elimi-nates the trauma and pain associated with injections. Furthermore, there is increased patient compliance. The purpose of this project was to study the effect of stainless steel microneedles on the transdermal de-livery of DH and PE.Method: We utilized vertical Franz diffusion cells to study in vitro transport of DH and PE across mi-croneedle-treated pig ear skin. Confocal laser scanning microscopy (CLSM) was used to characterize microchannel depth. Transdermal flux values were determined from the slope of the linear portion of the cumulative amount versus time curve.Results: There was a 113.59-fold increase in the transdermal permeation of DH following the application of microneedle roller compared to passive diffusion.Conclusion: In the case of PE, there was an 11.99-fold increase in the drug transport across pig skin following the application of microneedle rollers in comparison with passive diffusion. Student’s t-test and Mann-Whitney’s rank sum test were used to determine statistically significant differences between exper-imental and control groups

Combined use of biocompatible nanoemulsions and solid microneedles to improve transport of a model NSAID across the skin: In vitro and in vivo studies

This study aimed to investigate the potential of lecithin-based nanoemulsions costabilized by sucrose esters, with and without skin pretreatment with stainless steel microneedles, to improve delivery of aceclofenac, as a model drug, into/across the skin. The characterization revealed favorable droplet size (about 180 nm), narrow size distribution (<0.15), high surface charge (about −40 mV) and satisfying long-term stability (one year at 4 ± 1 °C) of the formulation costabilized by sucrose palmitate, demonstrating a similar trend observed for the reference stabilized by widely used lecithin/polysorbate 80 combination. In vitro release/permeation testing and differential stripping on the porcine ear proved the superiority of the sucrose ester- over polysorbate-based nanoemulsion. However, in vitro findings were not fully indicative of the in vivo performances – no significant differences were observed between investigated formulations in pharmacokinetic profile and total amount of aceclofenac deposited in the rat skin 24 h after dosing, simultaneously pointing to delayed aceclofenac delivery into the systemic circulation. In addition, the ratio of plasma concentrations of aceclofenac and its major metabolite in rats, diclofenac, was remarkably changed after topical application of tested nanoemulsions compared to intravenous administration of aceclofenac solution. Finally, skin pretreatment with microneedles improved aceclofenac delivery into/across the rat skin from tested formulations, resulting in 1.4–2.1-fold increased bioavailability and 1.2–1.7-fold enhanced level of aceclofenac retained in the skin, as measured 24 h after administration. Moreover, the plasma concentrations of aceclofenac 24 h after application of tested formulations (lecithin/sucrose palmitate vs. lecithin/polysorbate 80) combined with microneedles (173.37 ± 40.50 ng/ml vs. 259.23 ± 73.18 ng/ml) were significantly higher than those obtained through intact skin (105.69 ± 19.53 ng/ml vs. 88.38 ± 14.46 ng/ml). However, obtained results suggest that combination of microneedles and sucrose palmitate-costabilized nanoemulsion could be useful to attain higher skin concentration, while combination of microneedles with polysorbate 80-costabilized nanoemulsion could be a preferable option for enhancing drug delivery into the bloodstream.

Metallic microneedles with interconnected porosity: A scalable platform for biosensing and drug delivery

Metallic-based microneedles (MNs) offer a robust platform for minimally invasive drug delivery and biosensing applications due to their mechanical strength and proven tissue and drug compatibility. However, current designs suffer from limited functional surface area or challenges in manufacturing scalability. Here, porous 316L stainless steel MN patches are proposed. Fabricated through a scalable manufacturing process, they are suitable for storage and delivery of drugs and rapid absorption of fluids for biosensing. Fabrication of these MNs involves hot embossing a patch of stainless steel-based feedstock, sintering at 1100 °C and subsequent electropolishing. Optimisation of this manufacturing process yields devices that maintain mechanical integrity yet possess high surface area and associated porosity (36%) to maximise loading capacity. Similarly, a small pore size has been targeted (average diameter 2.22 μm, with 90% between 1.56 μm and 2.93 μm) to maximise capillarity and loading efficiency. This porous network has a theoretical wicking rate of 4.7 μl/s and can wick-up 27 ± 5 μl of fluid through capillary action which allows for absorption of pharmaceuticals for delivery. When inserted into a metabolite-loaded skin model, the MNs absorbed and recovered 17 ± 3 μl of the metabolite solution. The drug delivery performance of the porous metallic MNs (22.4 ± 4.9 µg/cm2) was found to be threefold higher than that of topical administration (7.1 ± 4.3 µg/cm2). The porous metallic MN patches have been shown to insert into porcine skin under a 19 N load. These results indicate the potential of design-for-manufacturing porous stainless steel MNs in biosensing and drug delivery applications. Statement of SignificanceMicroneedles are micro-scale sharp protrusions used to bypass the stratum corneum, the skin’s outer protective layer, and painlessly access dermal layers suitable for drug delivery and biosensing. Despite a depth of research in the area we have not yet seen large-scale clinical adoption of microneedle devices. Here we describe a device designed to address the potential barriers to adoption seen by other microneedles devices. We have developed a scalable, cost effective process to produce medical grade stainless steel microneedle patches which passively absorb and store drugs or interstitial fluid though a porous network and capillary action. This device, with low manufacturing and regulatory burdens may help the large-scale adoption of microneedles.