A Porous Microneedle Array Connected to Microfluidic System for ISF Collection

Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution

Microneedle (MN) arrays bypass the skin's stratum corneum barrier to deliver drugs directly into the viable tissue. The skin disposition of three types of MNs-dissolvable, degradable and hydrogel-forming, fabricated using different polymers-have been evaluated post-treatment with examples of these MN arrays and then examined by confocal Raman spectroscopy and stimulated Raman scattering (SRS) microscopy. The presence of the polymers was assessed from their characteristic Raman signals. SRS image mosaics were acquired to survey and visualise larger areas of the skin surface. After MN insertion, the skin's spectrum was acquired using confocal Raman spectroscopy at the surface, and at nominal depths of 50µm, 100µm, and 150µm. For dissolvable and degradable MNs, Raman signals from the constituent polymers were detectable in the skin. However, the polymer used to form the hydrogel MNs was not detectable under the experimental conditions used. SRS confirmed that the MN arrays penetrated the skin in a reasonably uniform manner. In summary, polymeric MN insertion into the skin has been visualised using confocal Raman spectroscopy and SRS microscopy. Together, these techniques have the potential to shed light on the spatial and temporal skin disposition of the constituent MN polymers used.

As the largest and most accessible organ in the body, with a surface area of 1.5–2 m 2 , the skin is an enticing target for drug delivery. Delivery of medication through the skin has expanded beyond the initial brief of topical delivery for local action to the transdermal application of drugs designed for systemic absorption and action. The principal obstacle to such transport is that of the stratum corneum, the outermost skin layer. To enable the delivery of a wider range of drug compounds and overcome the permeability barrier of the skin anatomy, microneedles (MNs) were born. MNs are a mechanical method of skin poration, first conceptualized in the 1970s [1]. Since manufacturing advances allowed the first practical realization in 1998 [2], MNs have demonstrated great promise as a novel drug delivery platform. MN arrays consist of a plurality of tiny projections on the micron scale arranged on a base plate. By bypassing the stratum corneum, its rate-controlling effect is nullified, allowing transdermal deliv ery of a much wider range of drug molecules than would be possible by passive diffusion, including macromolecules, such as biologics and vaccines. With a typical average length of 50–900 μm, MNs are long enough to penetrate to the dermis, but are short and narrow enough to avoid stimulation of dermal nerves or puncture of dermal blood vessels. Initially, MNs were typically prepared from silicon and metal. However, there is now great interest in the use of US FDA-approved polymeric materials for MN manufacture [3]. These materials are often inexpensive and widely available, amenable for MN manufacture without the use of harsh processing conditions, for example, elevated temperatures. Prepared from water-soluble polymers, dissolving MN arrays have the drug incorporated into the MN formulation and upon insertion, the MNs dissolve, releasing the drug in the viable skin layers. Such a strategy offers a number of advantages for the patient. As the MNs dissolve upon application, the dosage form is effectively self-disabling, meaning that not only is the reinsertion of the needles into another patient impossible, but there is also no risk of needle-stick injury to the healthcare professional, thereby reducing the overall risk of infection transmission. The question of disposal of MNs is also simplified, as with no sharp waste remaining, there is no need for safe disposal. Dissolving MN arrays have been used to deliver a range of compounds, from hydrophilic, low molecular weight drugs, to larger biopharmaceutical molecules, demonstrating the ability of such a platform to enhance transdermal delivery [4]. Indeed, the technology has progressed to human trials, with positive results recently published from a Phase 2a study for the delivery of human parathyroid hormone using a biodegradable MN technology called MicroCor ® , developed by Corium International, Inc. [5]. Another promising application for dissolving MNs is that of vaccination, capitalizing on the rich immune cell population in the skin,

Separable double-layered microneedle-based transdermal codelivery of DOX and LPS for synergistic immunochemotherapy of a subcutaneous glioma tumor

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

Arrays of microneedles (MNAs) are integrated in an out-of-plane fashion with a base plate and can serve as patches for the release of drugs and vaccines. We used soft-lithography and micromolding to manufacture ceramic nanoporous (np)MNAs. Failure modes of ceramic npMNAs are as yet poorly understood and the question remained: is our npMNA platform technology ready for microneedle (MN) assembly into patches? We investigated npMNAs by microindentation, yielding average crack fracture forces above the required insertion force for a single MN to penetrate human skin. We further developed a thumb pressure-actuated applicator-assisted npMNA insertion method, which enables anchoring of MNs in the skin by an adhesive in one handling step. Using a set of simple artificial skin models, we found a puncture efficiency of this insertion method a factor three times higher than by applying thumb pressure on the npMNA base plate directly. In addition, this new method facilitated zero MN-breakage due to a well-defined force distribution exerted onto the MNs and the closely surrounding area prior to bringing the adhesive into contact with the skin. Owing to the fact that such parameter space exists, we can conclude that npMNAs by soft lithography are a platform technology for MN assembly into a patch.

Hollow microneedle (MN) arrays offer versatility and control to transdermal drug delivery systems where a variety of drugs and their continuous supply are concerned. They may be used as a standalone device or be integrated with the drug reservoir or micropump. An important aspect in this regard is the effective fluidic communication between the reservoir and the MNs on a robust substrate. In a novel attempt of its kind, we present the development hollow SU-8 MNs on a pre-etched silicon wafer having through holes. SU-8 MNs are fabricated by direct laser writing by aligning them on the silicon substrate with microfluidic ports pre-etched by wet chemical etching. Each process step was optimized after a parametric study. The optimized MNs (500–600 µm length, 100 µm outer diameter and 40 µm inner diameter) have an aspect ratio of 5. The MNs have been characterized for mechanical strength and biological insertion tests for their effectiveness in puncturing the skin without breaking. The maximum compressive force and bending forces for the MNs are 0.27 N and 0.022 N per needle, which are higher than the resistive skin penetrating forces. The microfluidic characterizations show the development of hollow MN lumen with a flowrate of around 0.93 µl s−1 at 2 KPa pressure difference at the inlet. The array of 10 × 10 MNs with 500 µm spacing was able to successfully penetrate mice and rat skin without any breakage.

This study describes the processing of microneedle (MN) arrays with three different heights of arrowhead (600 µm (A1), 800 µm (A2), and 1000 µm (A3)), pyramid (600 µm (P1), 800 µm (P2), and 1000 µm (P3)), and turret (600 µm (T1), 800 µm (T2), and 1000 µm (T3)) designs using a digital light processing (DLP)-based 3D printing method. The 3D-printed MNs were examined for their morphological characteristics and mechanical performance. Scanning electron microscopy (SEM) imaging confirmed that all of the MNs were fabricated without fracture or bending. Each design exhibited distinct structural characteristics: arrowhead MNs displayed a well-defined morphology with sharp tips, pyramid MNs showed slight layering, and turret MNs, characterized by a wider base and sharp tips, had a smoother surface compared to the other designs. Mechanical tests revealed that the arrowhead MNs carried less load and were more prone to bending, while the pyramid and turret designs provided higher mechanical stability and penetration capacity. The pyramid design (P3) showed the highest mechanical strength, while turret MNs offered a more stable performance despite lower penetration capacity. These findings highlight the critical role of geometric design in optimizing MN performance for effective transdermal drug delivery.

Three-dimensional (3D) printing has transformed the development of microneedle arrays (MNAs) by enabling exceptional control over their geometry, distribution, materials, and functionality in a single-step, customizable process. This review represents a design-centric framework that organizes recent advancements in four interconnected levers: (i) individual microneedle (MN) geometry and size; (ii) patch-level MN distribution and multi-array architectures; (iii) computer-aided design (CAD), finite element analysis (FEA), computational fluid dynamics (CFD), and artificial intelligence/machine learning (AI/ML)-driven optimization; and (iv) manufacturing constraints and emerging solutions for scalability and reproducibility. Outcomes show that small changes in the radius of the MN’s tip, the MN’s aspect ratio, the MN’s internal lattice architecture, and the spacing of the array can dramatically influence their insertion force, mechanical reliability, payload capacity, and therapeutic coverage. Now, digital tools can bridge the design and experimental outcomes, while novel morphologies, hybrid materials, and theranostic integrations are expanding the clinical potential of MNs. The remaining challenges, resolution-versus-throughput trade-offs, biocompatibility, batch-to-batch consistency, and lack of testing standardization are examined alongside promising directions in high-throughput 3D printing, stimuli-responsive materials, and closed-loop systems. Finally, rational, model-guided design strategies are positioning 3D-printed MNAs as versatile platforms for painless, patient-specific drug delivery, diagnostics, and personalized medicine.

We describe formulation and evaluation of novel dissolving polymeric microneedle (MN) arrays for the facilitated delivery of low molecular weight, high dose drugs. Ibuprofen sodium was used as the model here and was successfully formulated at approximately 50% w/w in the dry state using the copolymer poly(methylvinylether/maleic acid). These MNs were robust and effectively penetrated skin in vitro, dissolving rapidly to deliver the incorporated drug. The delivery of 1.5mg ibuprofen sodium, the theoretical mass of ibuprofen sodium contained within the dry MN alone, was vastly exceeded, indicating extensive delivery of the drug loaded into the baseplates. Indeed in in vitro transdermal delivery studies, approximately 33mg (90%) of the drug initially loaded into the arrays was delivered over 24h. Iontophoresis produced no meaningful increase in delivery. Biocompatibility studies and in vivo rat skin tolerance experiments raised no concerns. The blood plasma ibuprofen sodium concentrations achieved in rats (263μgml−1 at the 24h time point) were approximately 20 times greater than the human therapeutic plasma level. By simplistic extrapolation of average weights from rats to humans, a MN patch design of no greater than 10cm2 could cautiously be estimated to deliver therapeutically-relevant concentrations of ibuprofen sodium in humans. This work, therefore, represents a significant progression in exploitation of MN for successful transdermal delivery of a much wider range of drugs.

Micropore closure kinetics are delayed following microneedle insertion in elderly subjects

Wound infections caused by invasive pathogens become an increasing global challenge health. Porous microneedles (MNs) present distinctive advantages for non‐invasive and in situ detection of wound infections, enabling the extraction of interstitial fluid, skin sweat, saliva and other biological samples. Consequently, porous MNs find widespread acceptance in medical detection, drug delivery, and monitoring physiological indicators. Based on these advantages, the emerging clinical applications and classifications of MNs is first introduced, covering mechanical strength, methods for antibody probe modification onto porous MNs, and signal amplification techniques for biomarkers analysis. At the same time, the specific applications of immunology and electrochemistry on porous MNs, introducing methods to enhance the detection signal of target molecules, such as rolling circle amplification, gold/silver nanoparticles, fluorescence amplification origami microneedle and so on is try to summarized. The improvement of detection sensitivity is realized by integrating various signal amplification strategies and diverse detection methods. Meanwhile, it is briefly illustrated applications in wound detections. Finally, challenges and future prospects of using porous MNs for detection in practical applications is discussed.

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.

Continuous glucose monitors have revolutionized diabetes management, yet such devices are limited by their cost, invasiveness, and stability. Microneedle (MN) arrays could offer improved comfort compared to invasive implanted or mm-sized needle devices, but such arrays are hampered by complex fabrication processes, limited mechanical and sensor stability, and/or cytotoxicity concerns. This work demonstrates the first crosslinked hydrogel microneedle-bioelectroenzymatic sensor arrays capable of biomarker extraction and robust transdermal continuous monitoring in artificial interstitial fluid for 10 days. The fabrication process via micromolding of dextran-methacrylate (Dex-MA) and dry-state visible light crosslinking is simple and permits the robust fixation of diverse prefabricated electrodes in a single array. Dry-state crosslinking minimized material shrinkage to enable the formation of resistant Dex-MA microneedles with shape control and reproducibility. The polymer substitution level (9-62%) and mass content (10-30wt%) affect the mechanical, swelling, and bioelectrocatalytic properties of the integrated sensors. Crosslinked Dex-MA hydrogel matrices provide beneficial cytotoxicity protection and flux-limiting membrane properties to the integrated second generation dehydrogenase-based nanostructured buckypaper biosensor and Ag/AgCl reference electrodes. Polysaccharide-based microneedle technology with encapsulated porous bioelectrodes promise to be a valuable alternative to more invasive devices for safer and longer-term biomarker monitoring.

Author: Please verify that the changes made to improve the English still retain your original meaning.Detection of microRNA (miRNA) in dermal interstitial fluid (ISF) has emerged as clinically useful in health status monitoring. However, it remains a great challenge owing to the difficult sampling and low abundance. Here, we report a DNA hydrogel microneedles (MNs) array to realize rapid enrichment and sensitive detection of miRNA in ISF. The MNs' patch consists of methacrylate hyaluronic acid (MeHA) equipped with a smart DNA circuit hydrogels' system (MeHA/DNA), in which an appropriate miRNA input enables triggering a cascading toehold-mediated DNA displacement reaction to catalytically cleave cross-linking points to generate amplified fluorescence (FL) for miRNA detection. The MeHA/DNA-MNs patch with high mechanical strength can extract adequate ISF in a short time (0.97 ± 0.2 mg in 5 min) in vivo because of its supreme water affinity. Additionally, the cascading toehold-mediated DNA displacement signal amplification reaction allows for sensitive detection of the low-abundant miRNAs down to 241.56 pM. The DNA hydrogels' MNs present potential for minimally invasive personalized diagnosis and real-time health monitoring in clinical applications.