Gelatin Methacryloyl Microneedle Patches for Minimally Invasive Extraction of Skin Interstitial Fluid

The extraction of interstitial fluid (ISF) from skin using microneedles (MNs) has attracted growing interest in recent years due to its potential for minimally invasive diagnostics and biosensors. ISF collection by absorption into a hydrogel MN patch is a promising way that requires the materials to have outstanding swelling ability. Here, a gelatin methacryloyl (GelMA) patch is developed with an 11 × 11 array of MNs for minimally invasive sampling of ISF. The properties of the patch can be tuned by altering the concentration of the GelMA prepolymer and the crosslinking time; patches are created with swelling ratios between 293% and 423% and compressive moduli between 3.34 MPa and 7.23 MPa. The optimized GelMA MN patch demonstrates efficient extraction of ISF. Furthermore, it efficiently and quantitatively detects glucose and vancomycin in ISF in an in vivo study. This minimally invasive approach of extracting ISF with a GelMA MN patch has the potential to complement blood sampling for the monitoring of target molecules from patients.     

Built-In Active Microneedle Patch with Enhanced Autonomous Drug Delivery

The use of microneedles has facilitated the painless localized delivery of drugs across the skin. However, their efficacy has been limited by slow diffusion of molecules and often requires external triggers. Herein, an autonomous and degradable, active microneedle delivery platform is introduced, employing magnesium microparticles loaded within the microneedle patch, as the built-in engine for deeper and faster intradermal payload delivery. The magnesium particles react with the interstitial fluid, leading to an explosive-like rapid production of H₂ bubbles, providing the necessary force to breach dermal barriers and enhance payload delivery. The release kinetics of active microneedles is evaluated in vitro by measuring the amount of IgG antibody (as a model drug) that passed through phantom tissue and a pigskin barrier. In vivo experiments using a B16F10 mouse melanoma model demonstrate that the active delivery of anti-CTLA-4 (a checkpoint inhibitor drug) results in greatly enhanced immune response and significantly longer survival. Moreover, spatially resolved zones of active and passive microneedles allow a combinatorial rapid burst response along with slow, sustained release, respectively. Such versatile and effective autonomous dynamic microneedle delivery technology offers considerable promise for a wide range of therapeutic applications, toward a greatly enhanced outcome, convenience, and cost.     

Microneedle Technologies for Food and Crop Health: Recent Advances and Future Perspectives

The global food supply constantly faces the threats of emerging crop diseases initiated by pathogens such as bacteria, fungi, and viruses. Plant diseases can cause significant economic and production losses in the agriculture industry, and early disease detection significantly mitigates losses. Monitoring the food quality and detecting pathogens during the food supply chain is essential in confirming the food's safety and reducing crop loss. This results in lowering production costs and increasing average yield in the agriculture industry. Considering the significant development of nanotechnology in biomedicine for human health monitoring, diagnostics, and treatment, there is an increasing interest in using nanotechnology in crop production, health, and plant science. This technology can allow continuous monitoring of plant health and on-site diagnostics of plant diseases. While many microneedle-based devices are previously reported for human health monitoring, diagnostics, and treatment, the application of this technology to agriculture started relatively recently. This review investigates the recent development of microneedle technology in food and crop health, where the most state-of-the-art microneedle-based devices are utilized for plant drug delivery, disease monitoring, and diagnosis. Finally, the current challenges and future directions in developing microneedle technology for food and crop health are discussed.     

Dissolving Microneedle Arrays for Transdermal Delivery of Amphiphilic Vaccines

Amphiphilic vaccine based on lipid‐polymer conjugates is a new type of vaccine capable of self‐delivering to the immune system. When injected subcutaneously, amphiphilic vaccines efficiently target antigen presenting cells in the lymph nodes (LNs) via a unique albumin‐mediated transport and uptake mechanism and induce potent humoral and cellular immune responses. However, whether this new type of vaccine can be administrated via a safe, convenient microneedle‐based transdermal approach remains unstudied. For such skin barrier‐disruption systems, a simple application of microneedle arrays (MNs) is desired to disrupt the stratum corneum, and for rapid and pain‐free self‐administration of vaccines into the skin, the anatomic place permeates with an intricate mesh of lymphatic vessels draining to LNs. Here the microneedle transdermal approach is combined with amphiphilic vaccines to create a simple delivery approach which efficiently traffic molecular vaccines into lymphatics and draining LNs. The rapid release of amphiphilic vaccines into epidermis upon application of dissolving MNs to the skin of mice generates potent cellular and humoral responses, comparable or superior to those elicited by traditional needle‐based immunizations. The results suggest that the amphiphilic vaccines delivered by dissolving MNs can provide a simple and safer vaccination method with enhanced vaccine efficacy.     

Spatiotemporal Catalytic Nanozymes Microneedle Patches with Opposite Properties for Wound Management

Reactive oxygen species (ROS)-mediated biological catalysis involves serial programmed enzymatic reactions and plays an important part against infectious diseases; while the spatiotemporal control of catalytic treatment to break the limitations of the disease microenvironment is challenging. Here, a novel spatiotemporal catalytic microneedles patch (CMSP-MNs) integrated with dual-effective Cu₂MoS₄ (CMS) and polydopamine (PDA) nanoparticles (NPs) for breaking microenvironment restrictions to treat wound infections is designed. Since CMS NPs are loaded in the needles, CMSP-MNs can catalytically generate diverse ROS to cause effective bacterial inactivation during bacterial infection process. Besides, PDA NPs are encapsulated in the backing layer, which facilitate ROS elimination and oxygen production for solving hypoxic problems in wound microenvironment and alleviating the expression of inflammatory factors during the inflammation process. Based on these features, it is demonstrated through cell and animal experiments that these nanozymes-integrated MNs patches can realize selective regulation of ROS level with bacterial inactivation and inflammatory treatment, resulting in minimized side effects of over-production ROS and effective anti-infected treatment. It is believed that the presented MNs can provide a new therapeutic strategy with spatiotemporal adjustable catalytic properties in biomedical areas.     

可生物降解高分子微针的制作及透皮应用

透皮给药相比于传统的给药方式,具有更多的优势．但是,皮肤的角质层能够阻止外源性物质的侵犯,限制了透皮给药系统的应用．为此,基于微针的透皮给药系统的提出增大了透皮给药系统的应用范围．首先,采用MEM技术制作单晶硅微针．接下来,提出一种新颖、简单而且经济的方法快速制作聚乳酸微针．通过理论分析及有限元分析微针的力学性能,表明微针有足够的强度．体外透皮实验表明,未经微针处理的皮肤,钙黄绿素10h的累计渗透量只有0．17±0．07 μg／cm2;手动进针处理的皮肤只达到4．54±1．17 μg／cm2,比未用微针处理的皮肤增加了30倍;经过进针器处理的皮肤,各个时间点的渗透量均有显著性提高（P〈0．05）,渗透量达到45．37±5．80 μg／cm2,比未用微针处理的皮肤增加了300倍．所有的结果都表明,本实验室制备可降解的聚乳酸微针的方法新颖、快速且经济,而且对于透皮给药系统来说具有很大的潜在价值．     

Glucose‐Responsive Composite Microneedle Patch for Hypoglycemia‐Triggered Delivery of Native Glucagon

Insulin‐dependent patients with diabetes mellitus require multiple daily injections of exogenous insulin to combat hyperglycemia. However, administration of excess insulin can lead to hypoglycemia, a life‐threatening condition characterized by abnormally low blood glucose levels (BGLs). To prevent hypoglycemia associated with intensive insulin therapy, a “smart” composite microneedle (cMN) patch is developed, which releases native glucagon at low glucose levels. The cMN patch is composed of a photo‐crosslinked methacrylated hyaluronic acid (MeHA) microneedle array with embedded multifunctional microgels. The microgels incorporate zwitterionic moieties that stabilize loaded glucagon and phenylboronic acid moieties that provide glucose‐dependent volume change to facilitate glucagon release. Hypoglycemia‐triggered release of structurally unchanged glucagon from the cMN patch is demonstrated in vitro and in a rat model of type 1 diabetes (T1D). Transdermal application of the patch prevented insulin‐induced hypoglycemia in the diabetic rats. This work is the first demonstration of a glucose‐responsive glucagon‐delivery MN patch for the prevention of hypoglycemia, which has a tremendous potential to reduce the dangers of intensive insulin therapy and improve the quality of life of patients with diabetes and their caregivers.     

Transdermal Delivery Devices: Fabrication,Mechanics and Drug Release from Silk

Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, the fabrication of dense microneedle arrays from silk with different drug release kinetics is reported. The mechanical properties of the microneedle patches are tuned by post‐fabrication treatments or by loading the needles with silk microparticles, to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs are delivered successfully. The various attributes demonstrated suggest that silk‐based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery.     

基于硅与非硅复合方法的异平面空心微针制作

为了解决制备空心微针工艺复杂且成本高的问题,本文提出了采用湿法刻蚀、光刻和电镀结合的方法制备低成本空心金属微针.首先采用湿法刻蚀硅,得到280μm深的倒四棱锥锥坑;然后在锥坑上甩200μm厚的负胶SU-8填充锥坑,并通过曝光显影负胶形成微针的形貌;最后在曝光显影后的负胶上电镀50μm厚的镍得到所需形状的空心金属微针.用此方法制备的空心微针高度为350μm、壁厚为50μm,其针尖形状为三棱锥和四棱锥.通过有限元仿真分析微针强度与微针结构尺寸的关系.用此方法加工出的微针具有锥形尖,改善了刺入皮肤的效果.     

Evaluation of the Transdermal Permeation Behavior of Proterguride from Drug in Adhesive Matrix Patches Through Hairless Mouse Skin

The transdermal in vitro permeation behavior of the highly potent dopamine agonist Proterguride was investigated using hairless mouse skin as a model membrane. Drug in adhesive matrix formulations based on different types of pressure-sensitive adhesives (Eudragit® E 100 and Gelva®7883 as acrylates, Oppanol® B 15 SFN as polyisobutylene, and BioPSA® 7-4202 as silicone) with a drug load of 3% by weight were manufactured. All patches were examined for drug crystallization by polarized microscopy immediately after the manufacturing process and after storage for 30 days in sealed aluminium laminate bags at ambient temperature and at 40°C, respectively. Furthermore, the influence of the drug load in acrylate-based formulations onto the steady-state flux of Proterguride was examined. The Eudragit® E 100 system delivered a significantly higher steady-state flux than the systems based on Oppanol® B 15 SFN and also a somewhat higher steady-state flux than the Gelva®-based patch. An addition of 10% by weight of the crystallization inhibitor povidone 25 did not significantly influence the steady-state flux of Proterguride from acrylate matrices. The lipophilic silicone and polyisobutylene adhesives facilitated drug crystallization within the short storage periods at both conditions, probably due to the absence of povidone 25, which was incompatible with these polymers. Varying the drug load in acrylate-based formulations led to a linear increase of the steady-state flux until the steady-state flux of Proterguride leveled off and the patches tended to drug crystallization. It was found that Gelva®-based patches show good physical stability, good skin adhesion, and moderate flux values and, thus, can be evaluated as a basis for a suitable formulation for the transdermal administration of Proterguride.     

一种用于药物释控系统的微针阵列及其制作方法的研究

 通过皮肤输送药物最大的障碍是皮肤最外层的角质层．传统的静脉注射用针只有刺透皮肤深入到深层组织内部,才能有效地输送药物,这容易引起感染和疼痛,给患者造成很大的不适．介绍了一种采用硅微加工技术制作的微针,它长度适中,既能穿透皮肤的角质层,又刺激不到深层组织的神经,实现无痛注射的目的．其加工工艺是采用硅的HNA(硝酸+氢氟酸+乙酸)腐蚀系统,是一种硅的各项同性的湿法腐蚀方法．     

Microneedles for transdermal drug delivery: a systematic review

Transdermal route has been explored for various agents due to its advantage of bypassing the first pass effect and sustained release of drug. Due to strong barrier properties of the skin, mainly stratum corneum (SC), the delivery of many therapeutic agents across the skin has become challenging. Few drugs with specific physicochemical properties (molecular weight <500?Da, adequate lipophilicity, and low melting point) can be effectively administered via transdermal route. However, delivery of hydrophilic drugs and macromolecular agents including peptides, DNA and small interfering RNA is challenging. Drug penetration through the SC may involve bypass or reversible disruption of SC layer by various means. Recently, the use of micron-scale needles has been proposed in increasing skin permeability and shown to dramatically increase permeation, especially for macromolecules. Microneedles (MNs) can penetrate through the SC layer of the skin into the viable epidermis, avoiding contact with nerve fibers and blood vessels that reside primarily in the dermal layer. This review summarizes the types of MNs and fabrication techniques of different types of MNs. The safety aspects of the materials used for fabrication have been discussed in detail. Biological applications and relevant phase III clinical trials are also highlighted.     

Controllable coating of microneedles for transdermal drug delivery

Coated microneedles have been paid much attention recently, and several coating strategies have been developed to address the problems during coating process. However, there are still some unresolved issues, such as, precise control requirements, microneedle substrate contamination and high processing temperature. The purpose of this study was to develop a simple and controllable method to make uniform coatings on microneedles at room temperature. This novel method avoids the contamination of microneedle substrate by providing both the adsorption force of thickener and micro-scale coating film produced by a newly design device. Thickeners were screened to enhance the mass of coatings. The parameters that influence the coatings were tested systematically, which made coating process controllable. Finally, three model drugs were coated onto microneedles to prove the method is applicable more broadly. In addition, insertion experiments were carried out to test the drug delivery feasibility of the coated microneedles. In conclusion, this study presents a simple and controllable method to coat microneedles with small molecular chemical drugs or large proteins for rapid skin drug delivery.