Nanosuspension-Loaded Dissolving Microneedle Patches for Enhanced Transdermal Delivery of a Highly Lipophilic Cannabidiol.

Purpose: Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum's barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility. Methods: Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance. Results: The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 ± 3.33 nm, a PDI of 0.21 ± 0.07, and a concentration of 46.11 ± 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action's duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-α and IL-1ß compared with the methotrexate subcutaneous injection method. Conclusion: NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration.

[Research advances of biomedical polymeric microneedles for non-transdermal local drug delivery].

Microneedles have emerged as the new class of local drug delivery system that has broad potential for development. Considering that the microneedles can penetrate tissue barriers quickly, and provide localized and targeted drug delivery, their applications have gradually expanded to non-transdermal drug delivery recently, which are capable of providing rapid and effective treatment for injuries and diseases of organs or tissues. However, a literature search revealed that there is a lack of summaries of the latest developments in non-transdermal drug delivery research by using biomedical polymeric microneedles. The review first described the materials and fabrication methods for the polymeric microneedles, and then reviewed a representative application of microneedles for non-transdermal drug delivery, with the primary focus being on treating and repairing the tissues or organs such as oral cavity, ocular tissues, blood vessels and heart. At the end of the article, the opportunities and challenges associated with microneedles for non-transdermal drug delivery were discussed, along with its future development, in order to provide reference for researchers in the relevant field.

Nanocarrier-Integrated Microneedles: Divulging the Potential of Novel Frontiers for Fostering the Management of Skin Ailments.

The various kinds of nanocarriers (NCs) have been explored for the delivery of therapeutics designed for the management of skin manifestations. The NCs are considered as one of the promising approaches for the skin delivery of therapeutics attributable to sustained release and enhanced skin penetration. Despite the extensive applications of the NCs, the challenges in their delivery via skin barrier (majorly stratum corneum) have persisted. To overcome all the challenges associated with the delivery of NCs, the microneedle (MN) technology has emerged as a beacon of hope. Programmable drug release, being painless, and its minimally invasive nature make it an intriguing strategy to circumvent the multiple challenges associated with the various drug delivery systems. The integration of positive traits of NCs and MNs boosts therapeutic effectiveness by evading stratum corneum, facilitating the delivery of NCs through the skin and enhancing their targeted delivery. This review discusses the barrier function of skin, the importance of MNs, the types of MNs, and the superiority of NC-loaded MNs. We highlighted the applications of NC-integrated MNs for the management of various skin ailments, combinational drug delivery, active targeting, in vivo imaging, and as theranostics. The clinical trials, patent portfolio, and marketed products of drug/NC-integrated MNs are covered. Finally, regulatory hurdles toward benchtop-to-bedside translation, along with promising prospects needed to scale up NC-integrated MN technology, have been deliberated. The current review is anticipated to deliver thoughtful visions to researchers, clinicians, and formulation scientists for the successful development of the MN-technology-based product by carefully optimizing all the formulation variables.

Advancements in microneedle fabrication techniques: artificial intelligence assisted 3D-printing technology.

Microneedles (MNs) are micron-scale needles that are a painless alternative to injections for delivering drugs through the skin. MNs find applications as biosensing devices and could serve as real-time diagnosis tools. There have been numerous fabrication techniques employed for producing quality MN-based systems, prominent among them is the three-dimensional (3D) printing. 3D printing enables the production of quality MNs of tuneable characteristics using a variety of materials. Further, the possible integration of artificial intelligence (AI) tools such as machine learning (ML) and deep learning (DL) with 3D printing makes it an indispensable tool for fabricating microneedles. Provided that these AI tools can be trained and act with minimal human intervention to control the quality of products produced, there is also a possibility of mass production of MNs using these tools in the future. This work reviews the specific role of AI in the 3D printing of MN-based devices discussing the use of AI in predicting drug release patterns, its role as a quality control tool, and in predicting the biomarker levels. Additionally, the autonomous 3D printing of microneedles using an integrated system of the internet of things (IoT) and machine learning (ML) is discussed in brief. Different categories of machine learning including supervised learning, semi-supervised learning, unsupervised learning, and reinforced learning have been discussed in brief. Lastly, a brief section is dedicated to the biosensing applications of MN-based devices.

Hollow silicon microneedles, fabricated using combined wet and dry etching techniques, for transdermal delivery and diagnostics.

Microneedle-based technologies are the subject of intense research and commercial interest for applications in transdermal delivery and diagnostics, primarily because of their minimally invasive and painless nature, which in turn could lead to increased patient compliance and self-administration. In this paper, a process for the fabrication of arrays of hollow silicon microneedles is described. This method uses just two bulk silicon etches - a front-side wet etch to define the 500 µm tall octagonal needle structure itself, and a rear-side dry etch to create a 50 µm diameter bore through the needle. This reduces the number of etches and process complexity over the approaches described elsewhere. Ex-vivo human skin and a customised applicator were used to demonstrate biomechanical reliability and the feasibility of using these microneedles for both transdermal delivery and diagnostics. Microneedle arrays show no damage even when applied to skin up to 40 times, are capable of delivering several mL of fluid at flowrates of 30 µL/min, and of withdrawing 1 µL of interstitial fluid using capillary action.

Design, fabrication, and characterisation of a silicon microneedle array for transdermal therapeutic delivery using a single step wet etch process.

The fabrication of silicon in-plane microneedle arrays from a simple single wet etch step is presented. The characteristic 54.7° sidewall etch angle obtained via KOH etching of (100) orientation silicon wafers has been used to create a novel microneedle design. The KOH simultaneously etches both the front and back sides of the wafer to produce V shaped grooves, that intersect to form a sharp pyramidal six-sided microneedle tip. This method allows fabrication of solid microneedles with different geometries to determine the optimal microneedle length and width for effective penetration and minimally invasive drug delivery. A modified grooved microneedle design can also be used to create a hollow microneedle, via bonding of two grooved microneedles together, creating an enclosed hollow channel. The microneedle arrays developed, effectively penetrate the skin without significant indentation, thereby enabling effective delivery of active ingredients via either a poke and patch application using solid microneedles or direct injection using hollow microneedles. This simple, scalable and cost effective method utilises KOH to etch the silicon wafer in-plane, allowing microneedles with variable length of several mm to be fabricated, as opposed to out-of-plane MNs, which are geometrically restricted to dimensions less than the thickness of the wafer. These microneedle arrays have been used to demonstrate effective delivery of insulin and hyaluronic acid into the skin.

Advances of Microneedles in Biomedical Applications.

A microneedle (MN) is a painless and minimally invasive drug delivery device initially developed in 1976. As microneedle technology evolves, microneedles with different shapes (cone and pyramid) and forms (solid, drug-coated, hollow, dissolvable and hydrogel-based microneedles) have been developed. The main objective of this review is the applications of microneedles in biomedical areas. Firstly, the classifications and manufacturing of microneedle are briefly introduced so that we can learn the advantages and fabrications of different MNs. Secondly, research of microneedles in biomedical therapy such as drug delivery systems, diagnoses of disease, as well as wound repair and cancer therapy are overviewed. Finally, the safety and the vision of the future of MNs are discussed.

An overview on the advantages and limitations of 3D printing of microneedles.

The use of 3D printing (3DP) technology, which has been continuously evolving since the 1980s, has recently become common in healthcare services. The introduction of 3DP into the pharmaceutical industry particularly aims at the development of patient-centered dosage forms based on structure design. It is still a new research direction with potential to create the targeted release of drug delivery systems in freeform geometries. Although the use of 3DP technology for solid oral dosage forms is more preferable, studies on transdermal applications of the technology are also increasing. Microneedle sequences are one of the transdermal drug delivery (TDD) methods which are used to bypass the minimally invasive stratum corneum with novel delivery methods for small molecule drugs and vaccines. Microneedle arrays have advantages over many traditional methods. It is attractive with features such as ease of application, controlled release of active substances and patient compliance. Recently, 3D printers have been used for the production of microneedle patches. After giving a brief overview of 3DP technology, this article includes the materials necessary for the preparation of microneedles and microneedle patches specifically for penetration enhancement, preparation methods, quality parameters, and their application to TDD. In addition, the applicability of 3D microneedles in the pharmaceutical industry has been evaluated.

Versatile Ice Microneedles for Transdermal Delivery of Diverse Actives.

Microneedles are regarded as an emerging and promising transdermal drug delivery strategy. Great efforts are devoted to getting rid of their material restrictions and imparting them with abilities to carry various drugs. Here, inspired by ice formation in nature and based on characteristics of different frozen materials, the authors present novel ice microneedles made from versatile soft materials using a simple freezing template-based fabrication stratagem for effective transdermal delivery of diverse actives. Their strategy can convert microneedles with almost all water-containing components from softness into hardness for guaranteeing satisfactory penetration, thus removing their material component limitations. As all fabrication procedures are mild and actives can maintain activity during these processes, the ice microneedles can carry and deliver various actives from small molecules and macromolecules to even living organisms. They have demonstrated that these ice microneedles can easily penetrate mouse and swine skins using a microneedle injector, with their active-carried tips left inside after their ice base melts. Thus, by loading heparin, erythropoietin, or biosafe Bacillus subtilis (B. subtilis) inside the ice microneedles to treat mouse models, the practical values of these microneedles are well displayed, indicating their bright prospects in universal drug delivery systems.

A Fully Integrated Closed-Loop System Based on Mesoporous Microneedles-Iontophoresis for Diabetes Treatment.

A closed-loop system that can mini-invasively track blood glucose and intelligently treat diabetes is in great demand for modern medicine, yet it remains challenging to realize. Microneedles technologies have recently emerged as powerful tools for transdermal applications with inherent painlessness and biosafety. In this work, for the first time to the authors' knowledge, a fully integrated wearable closed-loop system (IWCS) based on mini-invasive microneedle platform is developed for in situ diabetic sensing and treatment. The IWCS consists of three connected modules: 1) a mesoporous microneedle-reverse iontophoretic glucose sensor; 2) a flexible printed circuit board as integrated and control; and 3) a microneedle-iontophoretic insulin delivery component. As the key component, mesoporous microneedles enable the painless penetration of stratum corneum, implementing subcutaneous substance exchange. The coupling with iontophoresis significantly enhances glucose extraction and insulin delivery and enables electrical control. This IWCS is demonstrated to accurately monitor glucose fluctuations, and responsively deliver insulin to regulate hyperglycemia in diabetic rat model. The painless microneedles and wearable design endows this IWCS as a highly promising platform to improve the therapies of diabetic patients.

The role of microneedle arrays in drug delivery and patient monitoring to prevent diabetes induced fibrosis.

Diabetes affects approximately 450 million adults globally. If not effectively managed, chronic hyperglycaemia causes tissue damage that can develop into fibrosis. Fibrosis leads to end-organ complications, failure of organ systems occurs, which can ultimately cause death. One strategy to tackle end-organ complications is to maintain normoglycaemia. Conventionally, insulin is administered subcutaneously. Whilst effective, this delivery route shows several limitations, including pain. The transdermal route is a favourable alternative. Microneedle (MN) arrays are minimally invasive and painless devices that can enhance transdermal drug delivery. Convincing evidence is provided on MN-mediated insulin delivery. MN arrays can also be used as a diagnostic tool and monitor glucose levels. Furthermore, sophisticated MN array-based systems that integrate glucose monitoring and drug delivery into a single device have been designed. Therefore, MN technology has potential to revolutionise diabetes management. This review describes the current applications of MN technology for diabetes management and how these could prevent diabetes induced fibrosis.

Fabrication and characterisation of self-applicating heparin sodium microneedle patches.

The aim of this study was to develop heparin sodium loaded microneedle patches using different compositions of polyvinyl alcohol polymer and sorbitol. A vacuum micromolding technique was used to fabricate microneedle patches while heparin sodium was loaded into needle tips. Physical features of patches were evaluated by measuring thickness, width, folding endurance and swelling percentage. Patches were also characterised by optical microscopy and scanning electron microscopy to determine the microneedle length and surface morphologies. A preliminary assessment of the microneedle performance was studied by examining the in-vitro insertion to the parafilm and recording the in-vitro drug release profile. In-vivo activity of patches was confirmed by measuring activated partial thromboplastin time and histological examination of the micropierced skin tissues. Prepared patches were clear, smooth; uniform in appearance; with sharp pointed microprojections and remained intact after 1000 folding. The microneedles were stiffer in nature, as they reproduce microcavities in the parafilm membrane following hand pushing without any structural loss. Insertion study results showed successful insertion of microneedles into the parafilm. Disrupted stratum corneum evident from histological examination confirmed successful insertion of the microneedle without affecting the vasculature. In-vitro release study confirmed ∼92% release of the loaded drug within 120 min. A significant prolongation of activated partial thromboplastin time (4 folds as compared to negative control) was recorded following the application of heparin sodium loaded microneedle patch onto rabbit skin. In conclusion microneedles are a valuable drug delivery system, benefiting the patients with minimal skin invasion and also allowing self-administration of heparin sodium in a sustained release manner for the management of chronic ailments.

Influenza Vaccines toward Universality through Nanoplatforms and Given by Microneedle Patches.

Influenza is one of the top threats to public health. The best strategy to prevent influenza is vaccination. Because of the antigenic changes in the major surface antigens of influenza viruses, current seasonal influenza vaccines need to be updated every year to match the circulating strains and are suboptimal for protection. Furthermore, seasonal vaccines do not protect against potential influenza pandemics. A universal influenza vaccine will eliminate the threat of both influenza epidemics and pandemics. Due to the massive challenge in realizing influenza vaccine universality, a single vaccine strategy cannot meet the need. A comprehensive approach that integrates advances in immunogen designs, vaccine and adjuvant nanoplatforms, and vaccine delivery and controlled release has the potential to achieve an effective universal influenza vaccine. This review will summarize the advances in the research and development of an affordable universal influenza vaccine.

Electrospinning/electrospraying coatings for metal microneedles: A design of experiments (DOE) and quality by design (QbD) approach.

The research presented here shows QbD implementation for the optimisation of the key process parameters in electrohydrodynamic atomisation (EHDA). Here, the electrosprayed nanoparticles and electrospun fibers consisting of a polymeric matrix and dye. Eight formulations were assessed consisting of 5% w/v of polycaprolactone (PCL) in dichloromethane (DCM) and 5% w/v polyvinylpyrrolidone (PVP) in ethanol. A full factorial DOE was used to assess the various parameters (applied voltage, deposition distance, flow rate). Further particle and fiber analysis using Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared Spectroscopy (FTIR), particle/fiber size distribution. In addition to this in vitro release studied were carried out using fluorescein and Rhodamine B as model dyes and in vitro permeation studies were applied. The results show a significant difference in the morphology of resultant structures as well as a more rapid release profile for the PVP particles and fibers in comparison to the sustained release profiles found with PCL. In vitro drug release studies showed 100% drug release after 7 days for PCL particles and showed 100% drug release within 120 min for PVP particles. The release kinetics and the permeation study showed that the MN successfully pierced the membrane and the electrospun MN coating released a large amount of the loaded drug within 6 h. This study has demonstrated the capability of these robust MNs to encapsulate a diverse range drugs within a polymeric matrix giving rise to the potential of developed personalised medical devices.

Smart microneedle patches for rapid, and painless transdermal insulin delivery.

Insulin administration at mealtimes for the control of postprandial glucose is a major part of basal-bolus insulin therapy; however, painful subcutaneous (SC) injections lead to poor patient compliance. The microneedle (MN) patch, which allows painless transdermal drug delivery, is a promising substitute; however, it remains a big challenge to deliver insulin as rapidly as by SC injection. Here a novel MN patch is designed in which the MNs are coated with insulin/poly-l-glutamic acid (PGA) layer-by-layer (LBL) films at pH 3.0. This coating is pH-sensitive because the net charge of insulin turns from positive to negative when the pH increases from 3.0 to 7.4. As a result, when transferred to pH 7.4 media, e.g., when inserted into skin, the coating dissociates instantly and releases insulin rapidly. A brief epidermal application (<1 min) of the coated MNs is enough for complete film dissociation. More importantly, the coated MN patch exhibits a pharmacokinetic and a pharmacodynamic profile comparable to that of insulin administrated by SC injection, suggesting the coated MN patch can deliver insulin as rapidly as the SC injection. In addition, the patch exhibits excellent biocompatibility and storage stability. The new MN patch is expected to become a painless, convenient method for the control of postprandial glucose.

Vinpocetine loaded ultradeformable liposomes as fast dissolving microneedle patch: Tackling treatment challenges of dementia.

Vinpocetine (VPN) displays poor bioavailability (~7%) and short half-life (2-3 h) justifying the frequent dosing requirement of currently marketed oral tablets (thrice daily) and thus, posing a great challenge to patient compliance. Present work envisaged to achieve an infusion like delivery through transdermal route so as to tackle aforesaid challenges. With this aim, ultradeformable liposomes (UDL) incorporated fast dissolving microneedle patch (MNP) of VPN was developed and optimized for vesicle size and percent drug entrapment (critical quality attributes, CQA) utilizing the quality by design tool. Fractional factorial design followed by combined D-optimal design were applied to identify critical material attributes and obtain their statistically verified optimum levels (Phospholipon 90G, 15.17 mM; Phospholipon 90H, 4.83 mM; sodium deoxycholate, 15 mol% and Vinpocetine, 5 mol%) showing mean vesicle size of 75.65 nm and mean drug entrapment of 87.44%. An insignificant change in CQA of optimized UDL after incorporation in MNP further represented their physical compatibility with MNP components. In vitro characterization of these microneedles revealed rapid dissolution (~2 min) and good skin penetrability with around 0.684 N axial needle fracture force (ANFF). The safety was ascertained in vitro by exposing HaCaT cells to VPN UDL MNP components. A 94.27% cell viability advocated the safe nature of excipients used in formulation. Ex vivo permeation across full thickness pig ear skin revealed a steady state flux of 11.091 µg/cm2/h via VPN UDL MNP with around 9-fold enhancement when compared to flux value achieved through VPN suspension. In vivo pharmacokinetic and pharmacodynamic study in Sprague Dawley rats showed a 3-fold rise in relative bioavailability and a comparable mean escape latency via UDL MNP as compared to its oral suspension. In addition, half-life of 14 h and MRT of 21 h further confirmed the controlled release behavior of UDL MNP for prolonged period of time. In nutshell, the developed fast dissolving microneedle patch of VPN showed promising results with the prospect of lowering dose as well as dosing frequency for improved patient compliance.

The use of micro-needle arrays to deliver cells for cellular therapies.

Cell therapy is used to treat various diseases and to repair injuries. Cell delivery is a crucial process that delivers cells to target sites. Cells must be precisely delivered to a target site and the cells that are delivered must be localized to the target site to repair damaged tissue. For stem cell therapy, the most convenient method of cell delivery involves directly injecting cells into damaged tissue. Other strategies use carriers to transplant stem cells into damaged tissue. These are termed, stem cell delivery systems (SCDSs). Micro-needle arrays are minimally invasive transdermal delivery systems. The devices can pass through the stratum corneum barrier and deliver macromolecules into the skin. They can also access the microcirculation system in the skin. This study fabricates PMMA micro-needle using a two-stage micro-molding method. Cells are seeded on the micro-needle arrays and then transferred into the target tissue. Collagen hydrogel is used as a model biomimetic tissue. Cells are efficiently delivered to regions of interest, collagen hydrogel, by using this system. The delivery rate is about 83.2%. This demonstrates that micro-needle arrays allow very efficient delivery of cells.

Two-Photon Polymerisation 3D Printing of Microneedle Array Templates with Versatile Designs: Application in the Development of Polymeric Drug Delivery Systems.

PURPOSE: To apply a simple and flexible manufacturing technique, two-photon polymerisation (2PP), to the fabrication of microneedle (MN) array templates with high precision and low cost in a short time. METHODS: Seven different MN array templates were produced by 2PP 3D printing, varying needle height (900-1300 µm), shape (conical, pyramidal, cross-shaped and with pedestal), base width (300-500 µm) and interspacing (100-500 µm). Silicone MN array moulds were fabricated from these templates and used to produce dissolving and hydrogel-forming MN arrays. These polymeric MN arrays were evaluated for their insertion in skin models and their ability to deliver model drugs (cabotegravir sodium and ibuprofen sodium) to viable layers of the skin (ex vivo and in vitro) for subsequent controlled release and/or absorption. RESULTS: The various templates obtained with 2PP 3D printing allowed the reproducible fabrication of multiple MN array moulds. The polymeric MN arrays produced were efficiently inserted into two different skin models, with sharp conical and pyramidal needles showing the highest insertion depth values (64-90% of needle height). These results correlated generally with ex vivo and in vitro drug delivery results, where the same designs showed higher drug delivery rates after 24 h of application. CONCLUSION: This work highlights the benefits of using 2PP 3D printing to prototype variable MN array designs in a simple and reproducible manner, for their application in drug delivery.

A new oocyte-holding pipette for intracytoplasmic sperm injection without cytoplasmic aspiration: An experimental study in mouse oocytes.

We assessed the feasibility of using a new oocyte-holding pipette (pipette without aspiration, PiWA) for intracytoplasmic sperm injection (ICSI), which prevents cytoplasmic aspiration during microinjection. A pilot experimental study in eight mature mouse oocytes to assess the feasibility of the oocyte-holding PiWA for ICSI procedure. The absence of oocyte degeneration after microinjection and the viability of correct embryo development were also evaluated. The pipette comprises a suction conduit inside an elongated cylindrical body and a funnel-shaped working end, which is dimensioned to hold the oocyte in a tight-fitting manner. Upon aspirating via the suction conduit, the oocyte remains partially trapped inside the funnel and becomes deformed changing the spherical shape of its resting state to an oval shape that tensions the surface and increases the turgor. In all ICSI procedures using the new PiWA, the oocyte membrane presented some resistance but was easily broken when exerting some pressure or small aspiration. The eight oocytes developed, six of which reached the blastocyte stage. The results obtained in this study indicate that the increase in oocyte membrane turgidity caused by PiWA prevents vigorous aspiration of the cytoplasm during spermatozoa microinjection.

Customized fast-separable microneedles prepared with the aid of 3D printing for nanoparticle delivery.

3D printing of master molds for soft lithography-based fabrication of microneedles (MNs) is a cost effective, easy and fast method for producing MNs with variable designs. Deviating from the classical geometries of MNs, 'tanto blade'-inspired MNs showed effective skin penetration, acting as sharp structures with low insertion force of 10.6 N, which is sufficient for manual insertion. Additionally, hydrophilic, fluorescent noble metal nanocluster-modified gelatin nanocarriers were loaded in polyvinyl alcohol/sucrose MNs to act as a novel potential theranostic system emitting light in the near-infrared (λem = ~700 nm). Nanoparticles (NPs) distribution within the MNs and release have been monitored using confocal laser scanning microscopy by means of spectral analysis and linear unmixing. Furthermore, the MNs patch was modified by carving a channel at each of the four corners of the patch. This facilitated the separation process of MNs from the patch base into skin, when 15 µL phosphate buffered saline was applied through each channel post-skin insertion of the MNs. Then, the patch base can be removed easily leaving the implanted MNs inside the skin for further release of the NP cargo. This successfully reduced the application time to 1 min for enhanced patient compliance.