Macrophages play a pivotal role in the healing of diabetic ulcers. The sustained elevation of glucose levels damages the insulin signaling pathway in macrophages, leading to dysfunctional macrophages that struggle to transition from pro-inflammatory (M1) to reparative (M2) states. Therefore, modulating macrophage inflammatory responses via the insulin pathway holds promise for diabetic ulcer treatment. Additionally, the presence of biofilm impedes drug penetration, and the resulting immunosuppressive microenvironment exacerbates the persistent infiltration of pro-inflammatory M1 macrophages. Therefore, we designed an array of dissolvable microneedle (denoted as NPF@MN) loaded with self-assembled nanoparticles that could deliver NPF nanoparticles, acid-sensitive NPF-releasing Protocatechualdehyde (PA) with hypoglycemic and insulin-like effects, regulating macrophage polarization to an anti-inflammatory M2 phenotype. Additionally, this study extensively examined the mechanism by which NPF@MN accelerates the healing of diabetic ulcers through the activation of the insulin signaling pathway. Through RNA-seq and GSEA analysis, we identified a reduction in the expression of pathway-related factors such as IR, IRS-1, IRS-2, and SHC. Our work presents an innovative therapeutic approach targeting the insulin pathway in diabetic ulcers and underscores its translational potential for clinical management.

UNASSIGNED: Scar is an unpleasant skin lesion that occurs following deep wounds or burns. The application of local triamcinolone is a common treatment for scar treatment and prevention, which should be repeated several times in conventional dosage forms. An effort has been made here to provide a prolonged triamcinolone dermal delivery by microneedle technology, which can also be used for wound closure.
UNASSIGNED: This study aimed to develop a long-lasting polylactic acid (PLA) microneedle patch for the prolonged release of triamcinolone acetonide (TrA) that could potentially be used for closure of wound edges and scar prevention and treatment.
UNASSIGNED: In this study, 3% and 10% TrA-containing polymeric microneedles were fabricated using the micro molding-solvent casting method. Optical microscopy, X-ray diffraction analysis (XRD), Fourier-transform infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC) were used for the characterization of microneedles. Mechanical strength was evaluated using a compression test and methylene blue staining. Additionally, the insertion depth was determined by histopathological sectioning of human skin samples and also insertion into Parafilm®M as a skin model. The in vitro drug release profile of the microneedles was studied over 34 days, and the kinetic model was determined. The ex-vivo skin permeation of TrA was studied using a Franz-diffusion cell.
UNASSIGNED: The TrA-containing PLA microneedles were fabricated with a uniform structure without any failure, deterioration, or loss of needles. Fourier-transform infrared spectroscopy and differential scanning calorimetry showed no interaction between TrA and PLA, and no effect on crystallinity and thermal behavior of TrA on polymer was detected. Microneedles showed appropriate mechanical properties, which were able to penetrate to about 900 - 1000 μm depth. Release profile from the whole body of 10% and 3% microneedle fitted to Higuchi model with cumulative amounts of 625 µg and 201.64 µg over 34 days. Release from the needles followed zero-order kinetic with cumulative amounts of 30.04 µg and 20.36 µg for 10% and 3%, respectively, for 34 days. Permeation was calculated to be 17 µg/day for 10% TrA-containing microneedle.
UNASSIGNED: The results suggested that suitable PLA microneedles containing TrA with prolonged release behavior can be successfully constructed with the solvent casting method.

BACKGROUND: Anti-aging products are widely used, but the desire for safe and more efficient anti-aging products continues to increase. Dissolving microneedle patches (MNPs) have provided a more efficient transdermal drug delivery solution. MNP is a promising candidate for developing better anti-aging products.
OBJECTIVE: To develop a more efficient anti-aging MNP product, we fabricated a dual anti-wrinkle microneedle patch (named DA-MNP) using droplet extension (DEN®) technology and evaluated its skin puncture ability, safety, and efficacy through clinical studies.
METHODS: A DA-MNP comprising hyaluronic acid (HA) polymer backbone, acetyl octapeptide-3, and L-ascorbic acid 2-glucoside and sodium cyclic lysophosphatidic acid was fabricated using DEN® technology. Placebo MNPs comprising only HA were also fabricated. Twenty-four healthy subjects were enrolled in this comparative clinical study. The DA-MNP or placebo MNP was separately applied to the left and right eyes of subjects for overnight. Assessments, including wrinkle improvement, trans-epidermal water loss (TEWL), eye lifting and adverse effects were evaluated at each scheduled visit day for 28 days.
RESULTS: The DA-MNP showed mechanical strength enough for puncturing the stratum corneum. Compared to placebo MNP group, the DA-MNP treated group showed an effective eye wrinkles improvement and better anti-aging of skin, with reduced TEWL, enhanced skin elasticity and lifting, and no adverse effects.
CONCLUSIONS: The present study demonstrated that the fabricated DA-MNP exhibited fast acting on deep wrinkles and enhanced anti-aging efficacy, with no skin safety concern. Thus, this DA-MNP may serve as a new transdermal delivery solution for skin wrinkling and aging.

Microneedles are an innovation in the field of medicine that have the potential to revolutionize drug delivery, diagnostics, and cosmetic treatments. This innovation provides a minimally invasive means to deliver drugs, vaccines, and other therapeutic substances into the skin. This research investigates the design and manufacture of customized microneedle arrays using laser ablation. Laser ablation was performed using an ytterbium laser on a polymethyl methacrylate (PMMA) substrate to create a mold for casting polydimethylsiloxane (PDMS) microneedles. An experimental design was conducted to evaluate the effect of process parameters including laser pulse power, pulse width, pulse repetition, interval between pulses, and laser profile on the desired geometry of the microneedles. The analysis of variance (ANOVA) model showed that lasing interval, laser power, and pulse width had the highest influence on the output metrics (diameter and height) of the microneedle. The microneedle dimensions showed an increase with higher pulse width and vice versa with an increase in pulse interval. A response surface model indicated that the laser pulse width and interval (independent variables) significantly affect the response diameter and height (dependent variable). A predictive model was generated to predict the microneedle topology and aspect ratio varying from 0.8 to 1.5 based on the variation in critical input process parameters. This research lays the foundation for the design and fabrication of customized microneedles based on variations in specific input parameters for therapeutic applications in dermal sensors, drug delivery, and vaccine delivery.

Palatal injections are considered to be one of the most painful dental procedures. As a result, it was important to find alternatives to this painful injection to improve children\'s cooperation. The dental literature mentioned using EMLA cream as a possible alternative to conventional injections, but its anesthetic effect was debated. Therefore, it was valuable to research the impact of microneedle patches to enhance the effectiveness of this cream. The purpose of this randomized controlled clinical trial was to compare the effectiveness of different methods of anesthesia and pain levels in children aged 7-11 years. The study compared the use of EMLA cream, EMLA with microneedles, and conventional palatal injections. A total of 90 children were randomly assigned to three groups: Group 1 received conventional palatal anesthesia (control), Group 2 received EMLA cream only, and Group 3 received EMLA with microneedles. Pain levels were assessed using the FLACC and Wong-Baker scales at three different time points: T1(during anesthesia), T2(on palatal probing), and T3(during extraction). The FLACC scale revealed a significant difference in pain between groups only at T1 (P value = 0.000). It was found that the conventional palatal injection group had a higher pain level than the EMLA cream-only group and the group using microneedle patches with EMLA cream (P value = 0.000). However, the other groups did not show significant differences in pain levels during the anesthesia (P value  = 1.00). Similarly, the Wong-Baker scale also demonstrated a statistically significant difference in pain between groups only at T1 (P value  = 0.000). It was found that the conventional palatal injection group had a higher pain level than the EMLA cream-only group and the group using microneedle patches with EMLA cream (P value  = 0.000). However, the other groups did not show significant differences in pain levels during the anesthesia (P value  = 0.091). The study concludes that both EMLA cream alone and EMLA with microneedles can be used as an alternative to conventional palatal anesthesia for children.

Interstitial fluid (ISF) contains a wealth of biomolecules, yet it is underutilized for diagnostic testing due to a lack of rapid and simple techniques for collecting abundant amounts of fluid. Here, we report a simple and minimally invasive technique for rapidly sampling larger quantities of ISF from human skin. A microneedle array is used to generate micropores in skin from which ISF is extracted using a vacuum-assisted skin patch. Using this technique, an average of 20.8 μL of dermal ISF is collected in 25 min, which is an ∼6-fold improvement over existing sampling methods. Proteomic analysis of collected ISF reveals that it has nearly identical protein composition as blood, and >600 medically relevant biomarkers are identified. Toward this end, we demonstrate the detection of SARS-CoV-2 neutralizing antibodies in ISF collected from COVID-19 vaccinees using two commercial immunoassays, showcasing the utility of this technique for diagnostic testing.

Microneedles (MNs) have emerged as an innovative, virtually painless technique for intradermal drug delivery. However, the complex and costly fabrication process has limited their widespread accessibility, especially for individuals requiring frequent drug administration. This study introduces a groundbreaking and cost-effective method for producing MNs utilizing fused deposition modeling (FDM) 3D printing technology to enhance transdermal drug delivery. The proposed fabrication process involves the elongation of molten polylactic acid (PLA) filaments to create meticulously designed conoid and neiloid MNs with smooth surfaces. This study underscores the critical role of printing parameters, particularly extrusion length and printing speed, in determining the shape of the MNs. Notably, the conoid-shaped MNs exhibit exceptional skin-penetrating capabilities. In order to evaluate their effectiveness, the MNs were tested on a polydimethylsiloxane (PDMS) skin model for skin penetration. The results highlight the high potential of 3D-printed MNs for transdermal drug administration. This novel approach capitalizes on the benefits of 3D printing technology to fabricate MNs that hold the promise of transforming painless drug administration for a variety of medical applications.

Photothermolysis is the process that converts radiation energy into thermal energy, which results in the destruction of surrounding tissues or cells through thermal diffusion. Laser therapy that is based on photothermolysis has been a widely used treatment for various skin diseases such as skin cancers and port-wine stains. It offers several benefits such as non-invasiveness and selective treatment. However, the use of light, e.g., laser, for safe and effective photothermolysis becomes challenging due to the limited penetration of light into skin tissue as well as the presence of melanin, which absorbs this light. To solve the current issues, we propose an optical microneedle-lens array (OMLA) coated with gold in this work to directly deliver light to targeted skin layers without being absorbed by surrounding tissues as well as melanin, which results in the improvement of the efficiency of photothermal therapy. We developed a novel fabrication method, frame-guided micromolding, to prepare the OMLA by assembling two negative molds with simultaneous alignment. In addition, evaluations of the optical and heat transfer characteristics of the OMLA were performed. We expect our developed OMLA to play a crucial role in realizing more effective laser therapy by allowing the precise delivery of photons to the target area.

Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas.

Sealing of soft tissues prevents leakage of gas and liquid, closes wounds, and promotes healing and is, therefore, of great significance in the clinical and medical fields. Although various formulations have been developed for reliable sealing of soft tissue, tradeoffs between adhesive properties, degradation profile, and tissue toxicity limit their clinical use. Hydrogel-based adhesives, for example, are highly biocompatible but adhere very weakly to the tissue and degrade quickly, while oxidized cellulose patches are poorly absorbed and may cause healing complications postoperatively. Here, we present a novel strategy for tissue sealing based on bioadhesive microneedle patches that can spontaneously adhere to tissue surface through electrostatic interactions and swell within it. A series of microneedle patches made of pullulan, chitosan, Carbopol, poly (lactic-co-glycolic acid), and a Carbopol/chitosan combination were fabricated and characterized for their use in tissue sealing. The effect of microneedle composition on the fabrication process, physical and mechanical properties, in vitro cytotoxicity, and in vivo biocompatibility were examined. The needle structure enables microneedles to strongly fix onto various tissues via physical interlocking, while their adhesive properties improve staying time and sealing capabilities. The microneedle patch comprising Carbopol needles and chitosan as a second pedestal layer presented the best results in terms of sealing and adhesion, a consequence of the needle\'s swelling and adhesion features combined with the supportive chitosan base layer. Finally, single Carbopol/chitosan patches stopped intense liver bleeding in a rat model significantly quicker and with less blood loss compared with commercial oxidized cellulose patches. These microneedles can be considered a promising cost-effective platform for adhering and sealing tissues as they can be applied quickly and painlessly, and require less trained medical staff and equipment.