Impaired wound healing due to insufficient cell proliferation and angiogenesis is a significant physical and psychological burden to patients worldwide. Therapeutic delivery of exogenous growth factors (GFs) at high doses for wound repair is non-ideal as GFs have poor stability in proteolytic wound environments. Here, we present a two-stage strategy using bioactive sucralfate-based microneedle (SUC-MN) for delivering interleukin-4 (IL-4) to accelerate wound healing. In the first stage, SUC-MN synergistically enhanced the effect of IL-4 through more potent reprogramming of pro-regenerative M2-like macrophages via the JAK-STAT pathway to increase endogenous GF production. In the second stage, sucralfate binds to GFs and sterically disfavors protease degradation to increase bioavailability of GFs. The IL-4/SUC-MN technology accelerated wound healing by 56.6 % and 46.5 % in diabetic mice wounds and porcine wounds compared to their respective untreated controls. Overall, our findings highlight the innovative use of molecular simulations to identify bioactive ingredients and their incorporation into microneedles for promoting wound healing through multiple synergistic mechanisms.

Oral ulcers, superficial lesions on the surface of the oral mucosa, have a high incidence rate, and their main symptoms include local pain and erosion. Lipopolysaccharide (LPS)-preconditioned bone marrow mesenchymal stem cells and their secreted exosomes (LPS-pre-Exos) have been shown to promote recovery in various inflammatory conditions and wounds. However, studies documenting LPS-pre-Exos as a therapeutic intervention for oral mucosal-like diseases are lacking. In this study, we prepared a silk fibroin microneedle (MN) patch consisting of LPS-pre-Exos and zeolitic imidazolate framework-8 (ZIF-8) that localized at the tip and base, respectively, and used this MN patch for oral ulcer treatment. Upon insertion into the oral mucosa, continuous LPS-pre-Exos release was observed, which promoted macrophage polarization and tissue healing. Additionally, the ZIF-8 framework in the MN patch facilitated the controlled release of Zn2+, which demonstrated potent antimicrobial properties via synergistic effects. The in vitro experimental results showed that the silk fibroin MN patch can continuously release LPS-pre-Exos and Zn2+ for more than 7 days. Thus, the LPS-pre-Exos and ZIF-8-loaded silk fibroin MN patch exhibited good anti-inflammatory and antibacterial properties, promoting oral ulcer healing, and showed good histocompatibility. Hence, it may represent a potentially valuable strategy for facilitating oral ulcer healing.

Ophthalmic treatment demands precision and consistency in delivering therapeutic agents over extended periods to address many conditions, from common eye disorders to complex diseases. The diversity of conditions necessitates a range of delivery strategies, each tailored to specific needs. This comprehensive paper delves into various delivery cargos that are pivotal in ophthalmic care. These cargos encompass biodegradable implants that gradually release medication, nonbiodegradable implants for sustained drug delivery, refillable tools allowing flexibility in treatment, hydrogels capable of retaining substances while maintaining ocular comfort, and advanced nanotechnology devices that precisely target eye tissues. Within each cargo category, we explore cutting-edge research-level approaches and FDA-approved methods, providing a thorough overview of the current state of ophthalmic drug delivery. In particular, our focus on nanotechnology tools reveals the promising potential for gene delivery, cell therapy administration, and the implantation of active devices directly into the retina. These advancements hold the key to more effective, personalized, and minimally invasive ophthalmic treatments, revolutionizing the field of eye care.

Metformin is a medication that is commonly prescribed to manage type 2 diabetes. It has been used for more than 60 years and is highly effective in lowering blood glucose levels. Recent studies indicate that metformin may have additional medical benefits beyond treating diabetes, revealing its potential therapeutic uses. Oral medication is commonly used to administer metformin because of its convenience and cost-effectiveness. However, there are challenges in optimizing its effectiveness. Gastrointestinal side effects and limitations in bioavailability have led to the underutilization of metformin. Innovative drug-delivery systems such as fast-dissolving tablets, micro/nanoparticle formulations, hydrogel and microneedles have been explored to optimize metformin therapy. These strategies enhance metformin dosage, targeting, bioavailability and stability, and provide personalized treatment options for improved glucose homeostasis, antiobesity and metabolic health benefits. Developing new delivery systems for metformin shows potential for improving therapeutic outcomes, broadening its applications beyond diabetes management and addressing unmet medical needs in various clinical settings. However, it is important to improve drug-delivery systems, addressing issues such as complexity, cost, biocompatibility, stability during storage and transportation, loading capacity, required technologies and biomaterials, targeting precision and regulatory approval. Addressing these limitations is crucial for effective, safe and accessible drug delivery in clinical practice. In this review, recent advances in the development and application of metformin-delivery systems for diabetes and obesity are discussed.

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.

The Helicobacter pylori infection in the stomach is the key reason for gastric mucosal bleeding. Eliminating gastric Helicobacter pylori by oral treatment remains difficult due to the presence of the gastric mucosal layer, which acts as a physical barrier to drugs via oral administration. In this study, a magnetic-navigable microneedle drug delivery platform (MNsD) for oral administration, featuring differential dual-mode drug release rate, was designed to fulfil rapid gastric hemostasis and overcome the gastric barriers for long-lasting Helicobacter pylori inhibition in stomach. MNs-D was created by rationally loading the carrier substrate, which was composed of silk fibroin with variable solubility, with antibiotics and hemostats. In vitro experiments showed MNs-D may sustainably eradicate Helicobacter pylori in stimulated gastric juices with long-lasting drug release (79 % in 24 h) and quickly establish hemostasis with instant drug release (92 % within 60 s). Most importantly, in vivo studies demonstrated MNs-D overcame the unsettling gastric mucosal barrier in traditional therapies of oral administration by insertion into the GML under magnetic navigation, resulting in sustained antibiotic release for long-lasting Helicobacter pylori eradiation (99 %). For differential dual-mode medication release against gastric Helicobacter pylori infections, this study may have firstly examined the effects of magnetic navigated microneedles administered orally.

Neurological disorders, including brain injury, brain tumors, and neurodegenerative diseases, rank as the second leading cause of death worldwide. Exploring effective new treatments for neurological disorders has long been a hot research issue in clinical practice. Recently, microneedles (MNs) have attracted much attention due to their designation as a \"painless and non-invasive\" novel transdermal delivery method, characterized by their biocompatibility and sustainability. The advantages of MNs open an avenue for potential therapeutic interventions targeting neurological disorders. This review presents a concise overview of progress in the field of MNs, with highlights on the application in the treatment of neurological disorders. Notably, trends in the development of MNs and future challenges are also discussed.

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.

Cucurbit leaf crumple virus (CuLCrV) is among the prominent viruses infecting cucurbits in the USA. Attainable procedures of virus inoculation to crops are prerequisite for screening of resistance against the virus. Because mechanical (non-vector-mediated) infection by cucurbit leaf crumple virus (CuLCrV) is inefficient in economically important crops, screening for CuLCrV resistance is currently laborious and time-consuming using transmission by viruliferous whiteflies. We constructed an infectious partial tandem repeat construct of an isolate of CuLCrV from Georgia, USA, in the plant expression binary vector pCambia2300 and transformed it into Agrobacterium tumifaciens strain EHA105. Agroinfiltration of this construct into the abaxial surface of the leaves of common bean (Phaseolus vulgaris L.) produced a systemic infection characteristic of CuLCrV, although this approach was not successful for yellow squash. However, we report a very efficient and reproducible inoculation procedure established in squash when the leaves were injured with a microneedle and rubbed it with cell suspension harbouring the infectious viral construct.