Microneedle Delivery System Research Articles

Circadian Rhythm-Regulated ADSC-Derived sEVs and a Triphasic Microneedle Delivery System to Enhance Tendon-to-Bone Healing.

Modulating the inflammatory microenvironment to reconstruct the fibrocartilaginous layer while promoting tendon repair is crucial for enhancing tendon-to-bone healing in rotator cuff repair (RCR), a persistent challenge in orthopedics. Small extracellular vesicles (sEVs) hold significant potential to modulate inflammation, yet the efficient production of highly bioactive sEVs remains a substantial barrier to their clinical application. Moreover, achieving minimally invasive local delivery of sEVs to the tendon-to-bone interface presents significant technical difficulties. Herein, the circadian rhythm of adipose-derived stem cells is modulated to increase the yield and enhance the inflammatory regulatory capacity of sEVs. Circadian rhythm-regulated sEVs (CR-sEVs) enhance the cyclic adenosine monophosphate signaling pathway in macrophage (Mφ) via platelet factor 4 delivery, thereby inhibiting Mφ M1 polarization. Subsequently, a triphasic microneedle (MN) scaffold with a tip, stem, and base is designed for the local delivery of CR-sEVs (CR-sEVs/MN) at the tendon-to-bone junction, incorporating tendon-derived decellularized extracellular matrix in the base to facilitate tendon repair. CR-sEVs/MN mitigates inflammation, promotes fibrocartilage regeneration, and enhances tendon healing, thereby improving biomechanical strength and shoulder joint function in a rat RCR model. Combining CR-sEVs with this triphasic microneedle delivery system presents a promising strategy for enhancing tendon-to-bone healing in clinical settings.

Microneedle delivery system with rapid dissolution and sustained release of bleomycin for the treatment of hemangiomas

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.Graphical

Novel nano-in-micro fabrication technique of diclofenac nanoparticles loaded microneedle patches for localised and systemic drug delivery

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.

Rapamycin and HPPH Co-Loaded Nanodrug Delivered via Dissolvable Microneedles to Treat Port-Wine Stains

Port-wine stains are a kind of dermatological disease of congenital capillary malformation. Based on the biological characteristics of port-wine stains and the advantages of microneedle transdermal administration, we intend to construct a nanodrug co-loaded with rapamycin (RPM), an anti-angiogenesis drug, and photochlor (HPPH), a photosensitizer, and integrate the nanodrug with dissolvable microneedles (MN) to achieve anti-angiogenesis and photodynamic combination therapy for port-wine stains. First, RPM and HPPH co-loaded nanoparticles (RPM-HPPH NP) were prepared by the emulsification solvent-volatilization method, and its ability to generate reactive oxygen species (ROS) was investigated under 660 nm laser irradiation. Mouse hemangioendothelioma endothelial cells (EOMA) were used as the subjects of the study. The cellular uptake behaviors were examined by fluorescence microscopy and flow cytometry. The cytotoxicity effects of RPM-HPPH NP with or without 660 nm laser irradiation on EOMA cells were examined by MTT assays (with free RPM serving as the control). Then, hyaluronic acid (HA) dissolvable microneedles loaded with RPM-HPPH NP (RPM-HPPH NP@HA MN) were obtained by compounding the nanodrug with HA dissolvable microneedle system through the molding method. The morphological characteristics and mechanical properties of RPM-HPPH NP@HA MN were investigated by scanning electron microscope and electronic universal testing machine. The penetration ability of RPM-HPPH NP@HA MN on the skin of nude mice was evaluated by trypan blue staining and H&E staining experiment. The RPM-HPPH NP prepared in the study had a particle size of 150 nm and generated large amounts of ROS under laser irradiation. At the cellular level, RPM-HPPH NP was taken up by EOMA cells in a time-dependent manner. The cytotoxicity of RPM-HPPH NP was higher than that of free RPM with or without laser irradiation. Under laser irradiation, RPM-HPPH NP exhibited stronger cytotoxic effects and the difference was statistically significant (P<0.05). The height of the needle tip of RPM-HPPH NP@HA MN was 600 µm and the mechanical property of a single needle was 0.75048 N. Trypan blue staining and HE staining showed that pressing on the microneedles could produce pores on the skin surface and penetration of the stratum corneum. RPM-HPPH NP@HA MN can deliver RPM-HPPH NP percutaneously to the lesion tissue and realize the synergistic treatment of port-wine stains with anti-angiogenic therapy and photodynamic therapy, providing a new strategy for the construction of nanodrug-loaded microneedle delivery system and the clinical treatment of port-wine stains.

Progress on microneedle drug delivery systems for the treatment of corneal diseases

Corneal diseases are prevalent eye conditions in China, and the lack of effective treatment in the short term can lead to blindness. However, delivering drugs to the cornea safely and effectively poses a significant challenge due to the presence of ocular barriers and clearance mechanisms. Conventional drug delivery methods exhibit low bioavailability, making it difficult to achieve therapeutic effects. Microneedles, with their ability to penetrate ocular surface barriers effectively, offer a low-invasive and highly promising drug delivery technology. This article introduces the main delivery barriers on the ocular surface, classifies microneedles, and highlights the latest developments in the treatment of corneal diseases. Finally, the potential challenges of applying microneedle delivery systems to the ocular surface are analyzed, aiming to provide insights for the clinical application of microneedles in corneal diseases.

Competitive inhibition of nicotine acetylcholine receptors using microneedles of nicotine and varenicline for smoking withdrawal therapy

Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC and FDA. The available dosage forms for nicotine are patches, gums, inhalers and nasal sprays, bupropion and varenicline are available in tablet form. This research work focused on developing a microneedle delivery system to deliver combination drug for overcoming the obstacles encountered by oral route of administration of varenicline such as severe side effects (mood swings, agitation, depressed behaviour, seizures, etc), and nicotine therapy challenges such as short half-life, repeated dosing, nausea, and vomiting. The nanoparticles of nicotine prepared by nanoprecipitation method showed particle size PTZ (356.6 ± 65.98), percentage entrapment efficiency (35.55 % ± 0.007), in-vitro drug release (47.89 % ± 0.7) for 72 h. Microneedles showed height (600 μm), width (350 μm), and tip diameter (10 μm). The nanoparticles encapsulated in microneedles showed in-vitro sustained delivery of nicotine (67.00 % ± 4.92) and varenicline (79.78 % ± 1.09) in 48 h. Nicotine released in a sustained manner attaches to the nicotine acetylcholine receptors (nAchR) to release dopamine for controlling the withdrawal challenges such as anxiety, irritability, cravings, disturbed sleep pattern, etc. The varenicline released from microneedles binds to the nAchR and inhibits dopamine release responsible for the euphoric effect induced by nicotine, and thus assists in curbing the nicotine withdrawal symptoms. This combination microneedle system offers prolonged treatment in a single application for smoking withdrawal conditions wherein patients are not in stage of oral dosing because of repeated dosing resulting in adverse effects like seizures, hypertension, sleep disturbances, insomnia, and nausea.

Design, optimization, and evaluation for a long-time-released transdermal microneedle delivery system containing estradiol.

Transdermal drug delivery systems (TDDS) have drawbacks such as poor absorption, low blood concentration, and delayed effects. Dissolving microneedle has sharp tips and short length, which overcome patients' pain and improve transdermal efficiency but has low mechanical strength and drug loading capacity. This study thereby proposes a microemulsion-encapsulated and long-time-released transdermal microneedle (MN) delivery system with estradiol (Es) as the model drug. The microemulsion (ME) was optimized by utilizing the pseudo-ternary phase diagram and D-optimal mixture design. The estradiol microemulsion-encapsulated microneedle (Es-ME-MN) was optimized by Box-Behnken design and prepared by freeze-thaw method. The Es-ME-MN obtained was characterized and evaluated through a large variety of studies. Es-ME-MN had sufficient mechanical strength to pierce skin and was safe enough, the length of which was 600 μm, and the Es content was 177.12 ± 0.72 μg/patch without drug-excipient chemical interaction. In vitro permeation study showed that Es-ME-MN has a higher transdermal efficiency and lower retention capacity than commercial estradiol patch and conventional MN. Es plasma concentration began to increase at 3 h and remained at 12.98-23.52 ng/mL until 72 h by pharmacokinetic experiments in the Es-ME-MN group. Es-ME-MN rapidly achieves effective blood concentrations through needle puncture and microemulsion delivery and maintains blood concentrations through the baseplate long-time release. Microemulsion-encapsulated, organic solvent-free, and long-time-released transdermal microneedle will make progress and provide a new idea for transdermal delivery of lipophilic drugs.

A review Recent Advanced of Fabrication Techniques and Application of Micro-Needle

Micro-needles are micron-scaled medical devices used to administer vaccines, drugs, and other therapeutic agents. Micro-needles typically measure 0.1–1 mm in length. A variety of materials such as silicon, ceramic, stainless steel and polymers have been used for fabrication. Micro-needles devices are compatible with the delivery of both Small and macromolecular therapeutics. Micro-needles (MNs) are currently being utilized to enhance transdermal delivery of small and large molecules. With the emergence of micro fabrication manufacturing technology over the past several decades, (MNs) have been developed by academic laboratories and pharmaceutical companies. Micro-needle has useful in application in diseases such as type 2 Diabetes, cancer treatment, Glaucoma, and also useful application in cosmetic, vaccine therapy. The present article provides an overview of micro-needle, fabrication technique, general properties, Material and methods of fabrication techniques, application and advantages and disadvantages of micro-needle drug delivery system. Micro-needles (MNs) are currently being utilized to enhance trans-dermal delivery of small and large molecules. With the emergence of micro fabrication manufacturing technology over the past several decades, have been developed by academic laboratories and pharmaceutical companies.&#x0D;

Recent Trends in Macromolecule-Based Approaches for Hair Loss Treatment.

Macromolecules are large, complex molecules composed of smaller subunits known as monomers. The four primary categories of macromolecules found in living organisms are carbohydrates, lipids, proteins, and nucleic acids; they also encompass a broad range of natural and synthetic polymers. Recent studies have shown that biologically active macromolecules can help regenerate hair, providing a potential solution for current hair regeneration therapies. This review examines the latest developments in the use of macromolecules for the treatment of hair loss. The fundamental principles of hair follicle (HF) morphogenesis, hair shaft (HS) development, hair cycle regulation, and alopecia have been introduced. Microneedle (MN) and nanoparticle (NP) delivery systems are innovative treatments for hair loss. Additionally, the application of macromolecule-based tissue-engineered scaffolds for the in vitro and in vivo neogenesis of HFs is discussed. Furthermore, we explored a new research direction wherein artificial skin platforms are adopted as a promising screening method for hair loss treatment drugs. Through these multifaceted approaches, we identified promising aspects of macromolecules for future hair loss treatments. This article is protected by copyright. All rights reserved.

Responsive Microneedles as a New Platform for Precision Immunotherapy.

Microneedles are a well-known transdermal or transdermal drug delivery system. Different from intramuscular injection, intravenous injection, etc., the microneedle delivery system provides unique characteristics for immunotherapy administration. Microneedles can deliver immunotherapeutic agents to the epidermis and dermis, where immune cells are abundant, unlike conventional vaccine systems. Furthermore, microneedle devices can be designed to respond to certain endogenous or exogenous stimuli including pH, reactive oxygen species (ROS), enzyme, light, temperature, or mechanical force, thereby allowing controlled release of active compounds in the epidermis and dermis. In this way, multifunctional or stimuli-responsive microneedles for immunotherapy could enhance the efficacy of immune responses to prevent or mitigate disease progression and lessen systemic adverse effects on healthy tissues and organs. Since microneedles are a promising drug delivery system for accurate delivery and controlled drug release, this review focuses on the progress of using reactive microneedles for immunotherapy, especially for tumors. Limitations of current microneedle system are summarized, and the controllable administration and targeting of reactive microneedle systems are examined.

Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND)

HIV/AIDS remains a major global public health issue. While antiretroviral therapy is effective at reducing the viral load in the blood, up to 50% of those with HIV suffer from some degree of HIV-associated neurocognitive disorder, due to the presence of the blood–brain barrier restricting drugs from crossing into the central nervous system and treating the viral reservoir there. One way to circumvent this is the nose-to-brain pathway. This pathway can also be accessed via a facial intradermal injection. Certain parameters can increase delivery via this route, including using nanoparticles with a positive zeta potential and an effective diameter of 200 nm or less. Microneedle arrays offer a minimally invasive, pain-free alternative to traditional hypodermic injections. This study shows the formulation of nanocrystals of both rilpivirine (RPV) and cabotegravir, followed by incorporation into separate microneedle delivery systems for application to either side of the face. Following an in vivo study in rats, delivery to the brain was seen for both drugs. For RPV, a Cmax was seen at 21 days of 619.17 ± 73.32 ng/g, above that of recognised plasma IC90 levels, and potentially therapeutically relevant levels were maintained for 28 days. For CAB, a Cmax was seen at 28 days of 478.31 ± 320.86 ng/g, and while below recognised 4IC90 levels, does indicate that therapeutically relevant levels could be achieved by manipulating final microaaray patch size in humans.

Hyaluronic acid microneedles loaded with curcumin nanodrugs and new indocyanine green inhibits human tongue squamous carcinoma cells in vitro.

To prepare the hyaluronic acid microneedle (abbreviated as microneedle) delivery system carrying curcumin nanodrugs (Cur-NDs) and photothermal trigger agent new indocyanine green (IR820), and to investigate its effect on proliferation of human tongue squamous carcinoma cells (Cal-27) in vitro. The microneedle delivery system carrying Cur-NDs and IR820 was prepared. The morphological characteristics of the microneedles were observed, and the mechanical strength test, skin insertion ability test and the photothermal test in vitro were performed. Cal-27 cells were treated with microneedles, Cur-NDs microneedles, IR820 microneedles, or Cur-NDs+IR820 microneedles in vitro, respectively. The IR820 microneedle group and Cur-NDs+IR820 microneedle group were irradiated with 808 nm near infrared light at 1 W/cm 2 for 5 min. The cell viability was tested with cell counting kit-8 method. The prepared microneedles had homogeneous needle-like morphology, good mechanical strength and skin piercing ability, among which the microneedles equipped with IR820 showed better photothermal performance. The survival rates of Cal-27 cells were 100.00% in blank control group, 99.92% in control microneedles group, 94.08% in Cur-NDs microneedles group, 0.41% in IR820 microneedles group, and 0.04% in Cur-NDs+IR820 microneedles group, respectively (all P<0.05). Compared with single drug treatment, Cur-NDs+IR820 microneedle shows better inhibitory effect on Cal-27 cell proliferation in vitro.

Biologics‐Loaded Photothermally Dissolvable Hyaluronic Acid Microneedle Patch for Psoriasis Treatment

AbstractEmerging biologics, such as monoclonal antibodies (mAbs), are the most promising treatment for psoriasis, while their effective delivery to the local inflammatory area of the skin is a challenge. Here, a novel photo‐thermally dissolvable hyaluronic acid microneedle patch is presented with biologics IL‐17 mAbs and MXene encapsulation for psoriasis treatment. As the microneedles possess suitable mechanical strength and great biocompatibility, they can puncture the skin with minimal immune response. In addition, owing to the advantages of superior photothermal conversion efficiency of MXene additive, the microneedle patch can rapidly melt and release the encapsulated IL‐17 mAbs into the dermis under near‐infrared light irradiation for effective anti‐inflammatory effect around the psoriasis lesions. Based on these features, the multifunctional microneedle patch can effectively reduce psoriasis‐like skin inflammation in an imiquimod‐induced animal model, resulting in a desired therapeutic effect. Thus, the proposed microneedle delivery system provides a safer and effective strategy for psoriasis treatment, which is also valuable to improve the clinical efficacy of biologics‐based treatment for other chronic inflammatory autoimmune diseases.

Skin Patchable Sensor Surveillance for Continuous Glucose Monitoring.

Diabetes mellitus is a physiological and metabolic disorder affecting millions of people worldwide, associated with global morbidity, mortality, and financial expenses. Long-term complications can be avoided by frequent, continuous self-monitoring of blood glucose. Therefore, this review summarizes the current state-of-art glycemic control regimes involving measurement approaches and basic concepts. Following an introduction to the significance of continuous glucose sensing, we have tracked the evolution of glucose monitoring devices from minimally invasive to non-invasive methods to present an overview of the spectrum of continuous glucose monitoring (CGM) technologies. The conveniences, accuracy, and cost-effectiveness of the real-time CGM systems (rt-CGMs) are the factors considered for discussion. Transdermal biosensing and drug delivery routes have recently emerged as an innovative approach to substitute hypodermal needles. This work reviews skin-patchable glucose monitoring sensors for the first time, providing specifics of all the major findings in the past 6 years. Skin patch sensors and their progressive form, i.e., microneedle (MN) array sensory and delivery systems, are elaborated, covering self-powered, enzymatic, and non-enzymatic devices. The critical aspects reviewed are material design and assembly techniques focusing on flexibility, sensitivity, selectivity, biocompatibility, and user-end comfort. The review highlights the advantages of patchable MNs' multi-sensor technology designed to maintain precise blood glucose levels and administer diabetes drugs or insulin through a "sense and act" feedback loop. Subsequently, the limitations and potential challenges encountered from the MN array as rt-CGMs are listed. Furthermore, the current statuses of working prototype glucose-responsive "closed-loop" insulin delivery systems are discussed. Finally, the expected future developments and outlooks in clinical applications are discussed.

Microneedle systems for delivering nucleic acid drugs.

BackgroundNucleic acid-based gene therapy is a promising technology that has been used in various applications such as novel vaccination platforms for infectious/cancer diseases and cellular reprogramming because of its fast, specific, and effective properties. Despite its potential, the parenteral nucleic acid drug formulation exhibits instability and low efficacy due to various barriers, such as stability concerns related to its liquid state formulation, skin barriers, and endogenous nuclease degradation. As promising alternatives, many attempts have been made to perform nucleic acid delivery using a microneedle system. With its minimal invasiveness, microneedle can deliver nucleic acid drugs with enhanced efficacy and improved stability.Area coveredThis review describes nucleic acid medicines' current state and features and their delivery systems utilizing non-viral vectors and physical delivery systems. In addition, different types of microneedle delivery systems and their properties are briefly reviewed. Furthermore, recent advances of microneedle-based nucleic acid drugs, including featured vaccination applications, are described.Expert opinionNucleic acid drugs have shown significant potential beyond the limitation of conventional small molecules, and the current COVID-19 pandemic highlights the importance of nucleic acid therapies as a novel vaccination platform. Microneedle-mediated nucleic acid drug delivery is a potential platform for less invasive nucleic acid drug delivery. Microneedle system can show enhanced efficacy, stability, and improved patient convenience through self-administration with less pain.

Formulation Development and Improved Stability of a Combination Measles and Rubella Live-Viral Vaccine Dried for Use in the NanopatchTM Microneedle Delivery System

ABSTRACT Measles (Me) and rubella (Ru) viral diseases are targeted for elimination by ensuring a high level of vaccination coverage worldwide. Less costly, more convenient MeRu vaccine delivery systems should improve global vaccine coverage, especially in low – and middle – income countries (LMICs). In this work, we examine formulating a live, attenuated Me and Ru combination viral vaccine with Nanopatch™, a solid polymer micro-projection array for intradermal delivery. First, high throughput, qPCR-based viral infectivity and genome assays were established to enable formulation development to stabilize Me and Ru in a scaled-down, custom-built evaporative drying system to mimic the Nanopatch™ vaccine coating process. Second, excipient screening and optimization studies identified virus stabilizers for use during the drying process and upon storage in the dried state. Finally, a series of real-time and accelerated stability studies identified eight candidate formulations that met a target thermal stability criterion for live vaccines (<1 log10 loss after 1 week storage at 37°C). Compared to −80°C control samples, the top candidate formulations resulted in minimal viral infectivity titer losses after storage at 2–8°C for 6 months (i.e., <0.1 log10 for Me, and ~0.4 log10 for Ru). After storage at 25°C over 6 months, ~0.3–0.5 and ~1.0–1.4 log10 titer losses were observed for Me and Ru, respectively, enabling the rank-ordering of the stability of candidate formulations. These results are discussed in the context of future formulation challenges for developing microneedle-based dosage forms containing stabilized live, attenuated viral vaccines for use in LMICs.

Hyaluronic Acid-Mediated Drug Delivery System Targeting for Inflammatory Skin Diseases: A Mini Review.

Hyaluronic acid (HA), a major component of extracellular matrix has been widely applied in pharmaceutical and cosmetic industries due to its reported pharmacological properties. Various types of HA drug delivery system including nanoparticles, cryogel-based formulations, microneedle patches, and nano-emulsions were developed. There are studies reporting that several HA-based transdermal delivery systems exhibit excellent biocompatibility, enhanced permeability and efficient localized release of anti-psoriasis drugs and have shown to inhibit psoriasis-associated skin inflammation. Similarly HA is found in abundant at epidermis of atopic dermatitis (AD) suggesting its role in atopic AD pathology. Anti-allergenic effect of atopic eczema can be achieved through the inhibition of CD44 and protein kinase C alpha (PKCα) interaction by HA. Herein, we aim to evaluate the current innovation on HA drug delivery system and the other potential applications of HA in inflammatory skin diseases, focusing on atopic dermatitis and psoriasis. HA is typically integrated into different delivery systems including nanoparticles, liposomes, ethosomes and microneedle patches in supporting drug penetration through the stratum corneum layer of the skin. For instance, ethosomes and microneedle delivery system such as curcumin-loaded HA-modified ethosomes were developed to enhance skin retention and delivery of curcumin to CD44-expressing psoriatic cells whereas methotrexate-loaded HA-based microneedle was shown to enhance skin penetration of methotrexate to alleviate psoriasis-like skin inflammation. HA-based nanoparticles and pluronic F-127 based dual responsive (pH/temperature) hydrogels had been described to enhance drug permeation through and into the intact skin for AD treatment.

Clinical efficacy of dissolvable microneedles armed with anti-melanogenic compounds to counter hyperpigmentation.

Hyperpigmentation is a complex physiological process associated with alterations of skin color due to melanin overproduction and distribution. Both intrinsic and extrinsic factors influence discoloration with the involvement of multiple pathways in cooperative manners. Restoring natural skin color requires a multi-targeted approach. Latest advances in anti-melanogenic compounds and microneedle delivery system have presented opportunities for tackling hyperpigmentationsuccessfully. This work was aimed at assessing the dermal tolerability and efficacy of hyaluronic acid-based microneedle patches loaded with anti-melanogenic actives for improvements of skin discoloration. The test products consist of hyaluronic acid with niacinamide, ascorbic acid 2-glucoside, tranexamic acid, resveratrol, 4-n-butyl-resorcinol, and Halidrys siliquosa extract. In a monocentric 12weeks clinical trial, the HA-MNs patches were applied to the affected areas of the faces on subjects with hyperpigmented skin. The color properties of the skin were analyzed spectrophotometrically. The products were tolerated remarkably; none of the subjects informed any primary or cumulative skin responses. Evaluation of color related measurable skin properties provided insight into the general effectiveness: The individual topology measurements showed 51.4% noticeable improvements in hyperpigmented zones, which were also in good agreement with the personal impressions of the subjects determined by questionnaires before and after the treatments. The concentrated blends of actives in microneedle patches act in a multi-targeted manner, and they could be worked in a complementary fashion for the improvement of skin color and appearance. The study has established the overall convenience of the HA-MNs with the formulation of anti-melogenic compounds against skin discoloration.

Targeting proinsulin to local immune cells using an intradermal microneedle delivery system; a potential antigen-specific immunotherapy for type 1 diabetes

Antigen-specific immunotherapy (ASI) has been proposed as an alternative treatment strategy for type 1 diabetes (T1D). ASI aims to induce a regulatory, rather than stimulatory, immune response in order to reduce, or prevent, autoimmune mediated β-cell destruction, thus preserving endogenous insulin production. The abundance of immunocompetent antigen presenting cells (APCs) within the skin makes this organ an attractive target for immunotherapies. Microneedles (MNs) have been proposed as a suitable drug delivery system to facilitate intradermal delivery of autoantigens in a minimally invasive manner. However, studies to date have employed single peptide autoantigens, which would restrict ASI to patients expressing specific Human Leukocyte Antigen (HLA) molecules, thus stratifying the patient population. This study aims to develop, for the first time, an intradermal MN delivery system to target proinsulin, a large multi-epitope protein capable of inducing tolerance in a heterogeneous (in terms of HLA status) population of T1D patients, to the immunocompetent cells of the skin. An optimized three component coating formulation containing proinsulin, a diluent and a surfactant, facilitated uniform and reproducible coating of >30 μg of the active pharmaceutical ingredient on a stainless steel MN array consisting of thirty 500 μm projections. When applied to a murine model these proinsulin-coated MNs efficiently punctured the skin and after a limited insertion time (150 s) a significant proportion of the therapeutic payload (86%) was reproducibly delivered into the local tissue. Localized delivery of proinsulin in non-obese diabetic (NOD) mice using the coated MN system stimulated significantly greater proliferation of adoptively transferred antigen-specific CD8+ T cells in the skin draining lymph nodes compared to a conventional intradermal injection. This provides evidence of targeted delivery of the multi-epitope proinsulin antigen to skin-resident APCs, in vivo, in a form that enables antigen presentation to antigen-specific T cells in the local lymph nodes. The development of an innovative coated MN system for highly targeted and reproducible delivery of proinsulin to local immune cells warrants further evaluation to determine translation to a tolerogenic clinical outcome.

Microneedle System for Transdermal Drug and Vaccine Delivery: Devices, Safety, and Prospects.

Microneedle (MN) delivery system has been greatly developed to deliver drugs into the skin painlessly, noninvasively, and safety. In the past several decades, various types of MNs have been developed by the newer producing techniques. Briefly, as for the morphologically, MNs can be classified into solid, coated, dissolved, and hollow MN, based on the transdermal drug delivery methods of “poke and patch,” “coat and poke,” “poke and release,” and “poke and flow,” respectively. Microneedles also have other characteristics based on the materials and structures. In addition, various manufacturing techniques have been well-developed based on the materials. In this review, the materials, structures, morphologies, and fabricating methods of MNs are summarized. A separate part of the review is used to illustrate the application of MNs to deliver vaccine, insulin, lidocaine, aspirin, and other drugs. Finally, the review ends up with a perspective on the challenges in research and development of MNs, envisioning the future development of MNs as the next generation of drug delivery system.