Microneedle-based Device Research Articles

Characterising Skin Electrical Impedance Using Tape Stripping Methods: A Bioelectrical Study of a Porcine Model.

Background Recent advancements in ultra-low power electronics and wireless devices have facilitated the widespread adoption of wearable technology for fitness and health monitoring, paving the way for personalized medicine. Microneedle-based devices, comprising small epidermal patches that penetrate the skin's stratum corneum to potentially access biomarkers in the extracellular fluid of the viable epidermis, represent a promising innovation in this field. Objectives This project aimed to develop and validate a novel method to evaluate microneedle engagement in the skin in real-time. To our knowledge, there are no studies published to date that have characterized the electrical impedance of stratum corneum and epidermis using the tape stripping method to selectively remove cell layers. Additionally, no studies have been published comparing the electrical impedance of fresh to frozen-thawed porcine skin. The objective of this study was to develop and validate a novel method to evaluate microneedle engagement in skin, in real-time, that does not require processing of the tissue. Methods A tape stripping technique was employed to selectively remove the stratum corneum from fresh and frozen-thawed porcine skin samples which were then electrically characterized using an excitation frequency of 5 kHz with a peak Voltage of 1 V. Results This study demonstrated a mean impedance reduction of 97.08 ± 1.3 % for fresh porcine skin, and 98.04 ± 0.3 % for frozen-thawed porcine skin when transitioning from the surface stratum corneum to the viable epidermis. The correlation between the reduction of impedance and the number of tape strips across all 18 test sites was significant (r = 0.98, p < 0.00001). However, comparing the skin impedance of the fresh and frozen-thawed specimens showed poor equivalence, with the frozen-thawed sites approximately 5.5 times the impedance of the fresh sites before any tape stripping, and 4.19 times greater after 30 tape strips. Conclusions These findings suggest that monitoring for an interelectrode impedance decrease of greater than 95% between two projections of a microneedle device could provide a rapid and effective evaluation of skin engagement, crucial for advancing the development and clinical application of microneedle-based technologies in personalized medicine. The study also underscores the impact of the freeze-thaw process on the mechanical and electrical properties of skin, which is crucial for standardizing testing protocols.

Suprachoroidal Drug Delivery for Macular Edema Associated With Noninfectious Uveitis.

Purpose: To evaluate clinical trials in the literature that focus on suprachoroidal drug delivery for the treatment of noninfectious uveitis and other posterior segment diseases. Methods: A synthesis of the literature was performed. Results: In 2021, suprachoroidal space triamcinolone acetonide, a corticosteroid delivery system used for the treatment of uveitic macular edema (ME), was approved by the US Food and Drug Administration. The drug-delivery system targets the suprachoroidal space using a microneedle-based device and has a favorable pharmacokinetic profile. Suprachoroidally administered investigational therapies have also been assessed in clinical trials for other posterior segment diseases, including diabetic ME, retinal vein occlusion, age-related macular degeneration, and choroidal melanoma. Conclusions: The safety and efficacy of suprachoroidal corticosteroid injections to treat uveitic ME have been shown in recent phase III clinical trials. Multiple programs are also investigating this modality of drug delivery for use in many other retinal and choroidal pathologies.

Demonstrating the Analytical Potential of a Wearable Microneedle-Based Device for Intradermal CO2 Detection.

Monitoring of carbon dioxide (CO2) body levels is crucial under several clinical conditions (e.g., human intensive care and acid-base disorders). To date, painful and risky arterial blood punctures have been performed to obtain discrete CO2 measurements needed in clinical setups. Although noninvasive alternatives have been proposed to assess CO2, these are currently limited to benchtop devices, requiring trained personnel, being tedious, and providing punctual information, among other disadvantages. To the best of our knowledge, the literature and market lack a wearable device for real-time, on-body monitoring of CO2. Accordingly, we have developed a microneedle (MN)-based sensor array, labeled as CO2-MN, comprising a combination of potentiometric pH- and carbonate (CO32-)-selective electrodes together with the reference electrode. The CO2-MN is built on an epidermal patch that allows it to reach the stratum corneum of the skin, measuring pH and CO32- concentrations directly into the interstitial fluid (ISF). The levels for the pH-CO32- tandem are then used to estimate the PCO2 in the ISF. Assessing the response of each individual MN, we found adequate response time (t95 < 5s), sensitivity (50.4 and -24.6 mV dec-1 for pH and CO32-, respectively), and stability (1.6 mV h-1 for pH and 2.1 mV h-1 for CO32-). We validated the intradermal measurements of CO2 at the ex vivo level, using pieces of rat skin, and then, with in vivo assays in anesthetized rats, showing the suitability of the CO2-MN wearable device for on-body measurements. A good correlation between ISF and blood CO2 concentrations was observed, demonstrating the high potential of the developed MN sensing technology as an alternative to blood-based analysis in the near future. Moreover, these results open new horizons in the noninvasive, real-time monitoring of CO2 as well as other clinically relevant gases.

Microneedles: multifunctional devices for drug delivery, body fluid extraction, and bio-sensing

Microneedles represent a miniaturized mechanical structure with versatile applications including transdermal drug delivery, vaccination, body-fluid extraction, and bio-sensing. Over the past two decades, microneedle-based devices have garnered considerable attention in...

Wearable microneedle-based colorimetric and fluorescence sensing for transdermal diagnostics

Interstitial fluid is a readily accessible source of biomarkers for various diseases, providing a less invasive and more convenient option than traditional blood or tissue sampling methods. Microneedle-based point-of-care testing devices have gained significant interest due to their potential for direct detection of target analytes in ISF, accomplished through minimally invasive penetration of the stratum corneum. Thus, microneedle-based devices can be considered as adhesive tools for diagnostic sensing and therapeutic drug administration. Microneedle-based colorimetric and fluorescence sensing has the potential to revolutionize disease diagnosis and monitoring, offering a rapid, highly sensitive, specific, and cost-effective alternative to traditional methods. These devices enable the detection of low levels of biomarkers in the collected fluid, which is particularly important in situations requiring prompt diagnosis and treatment. This review covers the types of microneedles and their fabrication methods, the detection principles of microneedle-based colorimetric and fluorescence sensing, as well as their key applications, advantages, and limitations. Additionally, the review explores ways to overcome current limitations and improve the performance, as well as future perspectives for the development of microneedle-based devices.

Microneedle Device Delivering Aggregation-Induced Emission Photosensitizers for Enhanced Metronomic Photodynamic Therapy of Cancer.

Metronomic photodynamic therapy (mPDT), which induces cancer cell death by prolonged intermittent continuous irradiation at lower light power, has profoundly promising applications. However, the photobleaching sensitivity of the photosensitizer (PS) and the difficulty of delivery pose barriers to the clinical application of mPDT. Here, we constructed a microneedle-based device (Microneedles@AIE PSs) that combined with aggregation-induced emission (AIE) PSs to achieve enhanced mPDT for cancer. Due to the strong anti-photobleaching property of the AIE PS, it can maintain superior photosensitivity even after long-time light exposure. The delivery of the AIE PS to the tumor through a microneedle device allows for greater uniformity and depth. This Microneedles@AIE PSs-based mPDT (M-mPDT) offers better treatment outcomes and easier access, and combining M-mPDT with surgery or immunotherapy can also significantly improve the effectiveness of these clinical therapies. In conclusion, M-mPDT offers a promising strategy for the clinical application of PDT due to its better efficacy and convenience.

Wearable Clinic: From Microneedle-Based Sensors to Next-Generation Healthcare Platforms.

The rapid development of wearable biosensing calls for next-generation devices that allow continuous, real-time, and painless monitoring of health status along with responsive medical treatment. Microneedles have exhibited great potential for the direct access of dermal interstitial fluid (ISF) in a minimally invasive manner. Recent studies of microneedle-based devices have evolved from conventional off-line detection to multiplexed, wireless, and integrated sensing. In this review, the classification and fabrication techniques of microneedles are first introduced, and then the representative examples of microneedles for transdermal monitoring with different sensing modalities are summarized. State-of-the-art advances in therapeutic and closed-loop systems are presented to formulate guidelines for the development of next-generation microneedle-based healthcare platforms. The potential challenges and prospects are discussed to pave a new avenue toward pragmatic applications in the real world.

Suprachoroidal delivery enables targeting, localization and durability of small molecule suspensions.

Drug delivery to the suprachoroidal space (SCS®) has become a clinical reality after the 2021 FDA approval of CLS-TA, a triamcinolone acetonide injectable suspension for suprachoroidal use (XIPERE®), administered via a microneedle-based device, the SCS Microinjector®. Suprachoroidal (SC) delivery facilitates targeting, compartmentalization, and durability of small molecule suspensions, thereby potentially addressing some of the efficacy, safety, and treatment burden limitations of current retinal therapies. Herein, the design features of the SCS Microinjector are reviewed, along with the biomechanics of SC drug delivery. Also presented are preclinical evaluations of SC small molecule suspensions from 4 different therapeutic classes (plasma kallikrein inhibitor, receptor tyrosine kinase inhibitor, corticosteroid, complement factor D inhibitor), highlighting their potential for durability, targeted compartmentalization, and acceptable safety profiles following microinjector-based SC delivery. The clinical evaluations of the safety, tolerability and efficacy of SC delivered triamcinolone further supports potential of SC small molecule suspensions as a clinically viable strategy for the treatment of chorioretinal diseases. Also highlighted are current limitations, key pharmacological considerations, and future opportunities to optimize the SC microinjector platform for safe, effective, and potentially long-acting drug delivery for the treatment of chorioretinal disorders.

Microneedle-Based Device for Biological Analysis.

The collection and analysis of biological samples are an effective means of disease diagnosis and treatment. Blood sampling is a traditional approach in biological analysis. However, the blood sampling approach inevitably relies on invasive techniques and is usually performed by a professional. The microneedle (MN)-based devices have gained increasing attention due to their noninvasive manner compared to the traditional blood-based analysis method. In the present review, we introduce the materials for fabrication of MNs. We categorize MN-based devices based on four classes: MNs for transdermal sampling, biomarker capture, detecting or monitoring analytes, and bio-signal recording. Their design strategies and corresponding application are highlighted and discussed in detail. Finally, future perspectives of MN-based devices are discussed.

Lab under the Skin: Microneedle Based Wearable Devices.

While the current smartwatches and cellphones can readily track mobility and vital signs, a new generation of wearable devices is rapidly developing to enable users to monitor their health parameters at the molecular level. Within this emerging class of wearables, microneedle-based transdermal sensors are in a prime position to play a key role in synergizing the significant advantages of dermal interstitial fluid (ISF) as a rich source of clinical indicators and painless skin pricking to allow the collection of real-time diagnostic information. While initial efforts of microneedle sensing focused on ISF extraction coupled with either on-chip analysis or off-chip instrumentation, the latest trend has been oriented toward assembling electrochemical biosensors on the tip of microneedles to allow direct continuous chemical measurements. In this context, significant advances have recently been made in exploiting microneedle-based devices for real-time monitoring of various metabolites, electrolytes, and therapeutics and toward the simultaneous multiplexed detection of key chemical markers; yet, there are several grand challenges that still exist. In this review, we outline current progress, recent trends, and new capabilities of microneedle-empowered sensors, along with the current unmet challenges and a future roadmap toward transforming the latest innovations in the field to commercial products.

Microneedles for Extended Transdermal Therapeutics: A Route to Advanced Healthcare

Sustained release of drugs over a pre-determined period is required to maintain an effective therapeutic dose for variety of drug delivery applications. Transdermal devices such as polymeric microneedle patches and other microneedle-based devices have been utilized for sustained release of their payload. Swift clearing of drugs can be prevented either by designing a slow-degrading polymeric matrix or by providing physiochemical triggers to different microneedle-based devices for on-demand release. These long-acting transdermal devices prevent the burst release of drugs. This review highlights the recent advances of microneedle-based devices for sustained release of vaccines, hormones, and antiretrovirals with their prospective safe clinical translation.

Absorbent Microbiopsy Sampling and RNA Extraction for Minimally Invasive, Simultaneous Blood and Skin Analysis.

Conventional skin biopsy limits the clinical research that involves cosmetically sensitive areas or pediatric applications due to its invasiveness. Here, we describe the protocol for usingan absorbent microneedle-based device, absorbent microbiopsy, for minimally invasive sampling of skin and blood mixture. Our goal is to help facilitate rapid progress in clinical research, the establishment of biomarkers for skin disease and reducing the risk for clinical research participants. In contrast to conventional skin biopsy techniques, the absorbent microbiopsy can be performed within seconds and does not require intensive training due to its simple design. In this report, we describe the use of absorbent microbiopsy, including loading and application, on avolunteer. Then, we show how to isolate RNA from the absorbed sample. Finally, we demonstrate the use of quantitative reverse transcription PCR (RT-qPCR) to quantify mRNA expression levels of both blood (CD3E and CD19) and skin (KRT14 and TYR). The methods that we describe utilize off the shelf kits and reagents. This protocol offers a minimally invasive approach for simultaneous sampling of skin and blood within the same absorbent microbiopsy matrix. We have found human ethics committees, clinicians and volunteers to be supportive of this approach to dermatological research.

Acoustofluidics-based enzymatic constant determination by rapid and stable in situ mixing

Microfluidic mixings create considerable opportunities for microscale exploration of biomacromolecule function and local reaction kinetics. However, a robust and efficient way for localized mixing performance is not yet well established. In this study, we describe a simple and reliable method for rapid, stable, and controllable in situ mixing using a single-layer acoustofluidic system with a microneedle. We developed the single microstructure for region-confined mixing, which can be controlled dynamically by intentional acoustic activation. Various acoustofluidic impacts including driving frequency, microstructure design, driving voltage, and flow control on homogeneous mixing were systematically investigated. The microneedle-based device allows a fast (∼ 85 ms) mixing operation. Robust and high reusability of acoustofluidic system was experimentally demonstrated with up to 200 times of repetitive mixing and 100 min of continuous mixing. Furthermore, the proof-of-concept applications including real-time characterization of fluorescein quenching and β-glucuronidase-catalyzed hydrolysis of 4-methyl-umbelliferyl-β-d-glucuronide were successfully accomplished in the in situ mixing platform. We believe this microfluidic system could be suitable for investigation of different instantaneous chemical/biochemical events associated with various molecular interactions and reactions. Also, the acoustofluidic approach is potentially valuable to the development of mixing-based integrated microfluidic systems for applications in molecular science and life science.

Ocular drug delivery targeted by iontophoresis in the suprachoroidal space using a microneedle

Treatment of many posterior-segment ocular indications would benefit from improved targeting of drug delivery to the back of the eye. Here, we propose the use of iontophoresis to direct delivery of negatively charged nanoparticles through the suprachoroidal space (SCS) toward the posterior pole of the eye. Injection of nanoparticles into the SCS of the rabbit eye ex vivo without iontophoresis led to a nanoparticle distribution mostly localized at the site of injection near the limbus and <15% of nanoparticles delivered to the most posterior region of SCS (>9 mm from the limbus). Iontophoresis using a novel microneedle-based device increased posterior targeting with >30% of nanoparticles in the most posterior region of SCS. Posterior targeting increased with increasing iontophoresis current and increasing application time up to 3 min, but further increasing to 5 min was not better, probably due to the observed collapse of the SCS within 5 min after injection ex vivo. Reversing the direction of iontophoretic flow inhibited posterior targeting, with just ~5% of nanoparticles reaching the most posterior region of SCS. In the rabbit eye in vivo, iontophoresis at 0.14 mA for 3 min after injection of a 100 μL suspension of nanoparticles resulted in ~30% of nanoparticles delivered to the most posterior region of the SCS, which was consistent with ex vivo findings. The procedure was well tolerated, with only mild, transient tissue effects at the site of injection. We conclude that iontophoresis in the SCS using a microneedle has promise as a method to target ocular drug delivery within the eye, especially toward the posterior pole.

Microneedle-based device for the one-step painless collection of capillary blood samples.

The advancement of point-of-care diagnostics and the decentralization of healthcare have created a need for the simple, safe, standardized and painless collection of blood specimens. Here, we describe the design and implementation of a capillary blood-collection device that is more convenient and less painful than a fingerstick and venepuncture, and collects 100 µl of blood. The technology integrates into a compact, self-contained device an array of solid microneedles, a high-velocity insertion mechanism, stored vacuum, and a microfluidic system containing lithium heparin anticoagulant. The use of the device requires minimal training, as blood collection is initiated by the single push of a button. In a clinical study involving 144 participants, haemoglobin A1c measurements from device-collected samples and from venous blood samples were equivalent, and the pain associated with the device was significantly less than that associated with venepuncture. The device, which has received premarket clearance by the US Food and Drug Administration, should help improve access to healthcare, and support healthcare decentralization.

Integrated Lithographic Molding for Microneedle-Based Devices

This paper presents a new fabrication method consisting of lithographically defining multiple layers of high aspect-ratio photoresist onto preprocessed silicon substrates and release of the polymer by the lost mold or sacrificial layer technique, coined by us as lithographic molding. The process methodology was demonstrated fabricating out-of-plane polymeric hollow microneedles. First, the fabrication of needle tips was demonstrated for polymeric microneedles with an outer diameter of 250 mum, through-hole capillaries of 75-mum diameter and a needle shaft length of 430 mum by lithographic processing of SU-8 onto simple v-grooves. Second, the technique was extended to gain more freedom in tip shape design, needle shaft length and use of filling materials. A novel combination of silicon dry and wet etching is introduced that allows highly accurate and repetitive lithographic molding of a complex shape. Both techniques consent to the lithographic integration of microfluidic back plates forming a patch-type device. These microneedle-integrated patches offer a feasible solution for medical applications that demand an easy to use point-of-care sample collector, for example, in blood diagnostics for lithium therapy. Although microchip capillary electrophoresis glass devices were addressed earlier, here, we show for the first time the complete diagnostic method based on microneedles made from SU-8.

Microneedle-Based Intradermal Delivery of the Anthrax Recombinant Protective Antigen Vaccine

The recombinant protective antigen (rPA) of Bacillus anthracis is a promising anthrax vaccine. We compared serum immunoglobulin G levels and toxin-neutralizing antibody titers in rabbits following delivery of various doses of vaccine by microneedle-based intradermal (i.d.) delivery or intramuscular (i.m.) injection using conventional needles. Intradermal delivery required less antigen to induce levels of antibody similar to those produced via i.m. injection during the first 2 weeks following primary and booster inoculation. This dose-sparing effect was less evident at the later stages of the immune response. Rabbits immunized i.d. with 10 mug of rPA displayed 100% protection from aerosol spore challenge, while i.m. injection of the same dose provided slightly lower protection (71%). Groups immunized with lower antigen doses were partially protected (13 to 29%) regardless of the mode of administration. Overall, our results suggest rPA formulated with aluminum adjuvant and administered to the skin by a microneedle-based device is as efficacious as i.m. vaccination.