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Sulfur mustard (2,2′-dichloroethylsulfide; SM) is a bifunctional alkylating agent that can easily penetrate skin and cause persistent pain and damage. Effective biological dressings are required to treat wounds caused or poisoned by SM. Though the use of SM is regulated under the Chemical Weapons Convention, it is still a threat during wars and terrorist attacks. Herein, we present a photothermal-enhanced detoxification microneedles array (MNA) encapsulated with ZnIn2S4@UiO-66-NH2 (ZnInS/UIO) catalysts for the treatment of 2-chloroethyl ethyl sulfide (CEES, SM analog)-poisoned wounds under simulated sunlight (SSL) irradiation. Due to the excellent photothermal detoxification capability possessed by ZnInS/UIO, the conversion rate of CEES can be significantly increased under SSL exposure. When encased in a polyvinyl alcohol (PVA) MNA and piercing into the skin, ZnInS/UIO catalysts can be released quickly from MNA for detoxification. After applying the resultant ZnInS/UIO-MNA to the CEES-poisoned wound bed, acceleration of the wound healing process and a reduced inflammatory response can be confirmed. In conclusion, ZnInS/UIO-MNA has encouraging potential as a first-aid dressing for CEES-poisoned wound healing in battlefields and injuries related to acts of terrorism.

Objective: To evaluate the efficacy of CO2 fractional laser and microneedling pretreatment combined with ALA-PDT for moderate-to-severe acne, aiming to optimize clinical treatment. Methods: Patients were randomly divided into three groups: Group A (CO2 fractional laser + ALA-PDT), Group B (microneedling + ALA-PDT), and Group C (ALA-PDT). Each group underwent photodynamic therapy once a week for 3 weeks. Efficacy was assessed at the end of the 4th week, and recurrence was assessed at the end of the 12th week. Results: A total of 150 patients with moderate to severe acne were included in this study, with 50 patients in each group. Four weeks after the end of treatment, the effective rates were 88 % for Group A, 62 % for Group B, and 36 % for Group C. Statistically significant differences were found between the groups (P < 0.05), with Group A showing superior efficacy compared to Group B (P < 0.05). No serious systemic or local adverse reactions were observed in any group. No recurrence was seen in any group 12 weeks after the end of treatment, and some patients continued to show improvement in skin lesions over time. Conclusion: Both the CO2 fractional laser group and the microneedling group improved the efficacy of photodynamic therapy for moderate to severe acne compared to the control group, with the CO2 fractional laser group demonstrating better efficacy and fewer adverse effects.

Vitamin C (VIT C) is an antioxidant that prevents skin aging. Although dermal delivery is one of the most effective routes to transport VIT C to the skin, the impact of this route can be limited by the barrier function of the stratum corneum (SC). Additionally, VIT C rapidly oxidized and degraded under light and temperature. Therefore, this study provides an approach to utilizing microneedles (MNs) to improve the dermal delivery of VIT C and enhance its stability by incorporating a stabilizing system of ethylenediaminetetraacetic acid (EDTA) and sodium metabisulfite (Meta) within the MNs. Vitamin C microneedles (VIT C MNs) were fabricated using different biodegradable polymers and various concentrations of EDTA/Meta. VIT C MNs were evaluated for morphology, VIT C content, mechanical properties, dissolution rate, needles’ insertion, physicochemical properties, ex vivo permeation, viscosity of VIT C polymeric solutions, cytotoxicity, and stability. The results showed that VIT C MNs were uniform and mechanically strong. The recovery of VIT C in MNs was 88.3–90.0 %. The dissolution rate of MNs was

Bacterial infections are mainly managed by the administration of antibiotics, which are either cytotoxic or cytostatic to microbes. In some cases, it is inconvenient to treat infections caused by bacteria using the traditional oral route for antibiotic administration. This can be due to the limited oral bioavailability of antibiotics, their gastrointestinal tract (GIT) adverse effects, and the increased possibility of the appearance of resistant strains. In addition, the fact that many populations are needle-phobic restricts the switch from the oral to the parenteral route. Furthermore, poor drug permeation throughout the stratum corneum of topically applied antibiotics causes low systemic bioavailability. Therefore, microneedles (MNs) have emerged as viable medicinal devices for the delivery of antibiotics, either for local or systemic effects. MNs represent a minimally invasive, painless way of administration that can be self-administered by the patient without the need of medical professionals. This review has specifically focused on MNs as a promising approach for the delivery of antibiotics; it has discussed the different types of MNs, their advantages, and possible limitations for the delivery of antibiotics. Recent studies on the incorporation of antibiotics into various types of MNs, either for topical or transdermal delivery are highlighted, and finally, we present the conclusion and future perspectives.

Nowadays, microneedles as novel transdermal delivery systems are interested in scientists for biomedical applications. This work aims to present a Cascade Microneedle Molding Technique (CMMT) for the reusable fabrication of polydimethylsiloxane (PDMS) molds to produce microneedle devices. To produce a positive master mold from epoxy resin, a negative PDMS mold was first fabricated. PDMS can be molded, and microneedles can be fabricated using this epoxy mold in a scalable and cost-effective manner. These molds were used to manufacture solid, coated, and dissolving microneedles, which were characterized comprehensively. Microneedle morphology and geometry were evaluated using Scanning Electron Microscopy (SEM). The mechanical integrity and ability to insert the microneedle device into the skin were assessed using compression strength analysis and force-displacement measurements. Drug penetration through animal skin was evaluated for Rhodamine B (RhB) loaded microneedles. The depth of needle insertion was also visualized using histological analysis while the spatial distribution of released cargo was determined by using confocal microscopy. Taken together, CMMT offers a simple, rapid, cost-effective, and scalable method for mass-producing microneedles with remarkable properties compared to direct 3D printing or laser ablation.

Joint injuries are among the leading causes of disability. Present concentrations were focused on oral drugs and surgical treatment, which brings severe and unnecessary difficulties for patients. Smart patches with high flexibility and intelligent drug control-release capacity are greatly desirable for efficient joint management. Herein, we present a novel kirigami spider fibroin-based microneedle triboelectric nanogenerator (KSM-TENG) patch with distinctive features for comprehensive joint management. The microneedle patch consists of two parts: the superfine tips and the flexible backing base, which endow it with great mechanical strength to penetrate the skin and enough flexibility to fit different bends. Besides, the spider fibroin-based MNs served as a positive triboelectric material to generate electrical stimulation, thereby forcing drug release from needles within 720 min. Especially, kirigami structures could also transform the flat patch into three dimensions, which could impart the patch with flexible properties to accommodate the complicated processes produced by joint motion. Benefiting from these traits, the KSM-TENG patch presents excellent performance in inhibiting the inflammatory response and promoting wound healing in mice models. The results indicated that the mice possessed only 2% wound area and the paw thickness was reduced from 10.5 mm to 6.2 mm after treatment with the KSM-TENG patch, which further demonstrates the therapeutic effect of joints in vivo. Thus, it is believed that the proposed novel KSM-TENG patch is valuable in the field of comprehensive treatments and personalized clinical applications.

Microneedles (MNs) can be used for the topical treatment of skin disorders as they directly deliver therapeutics to the site of skin lesions, resulting in increased therapeutic efficacy while having minimum side effects. MNs are used to deliver different kinds of therapeutics (e.g., small molecules, macromolecules, nanomedicines, living cells, bacteria, and exosomes) for treating various skin disorders, including superficial tumors, wounds, skin infections, inflammatory skin diseases, and abnormal skin appearance. The therapeutic efficacy of MNs can be improved by integrating the advantages of multiple therapeutics to perform combination therapy. Through careful designing, MNs can be further modified with biomimetic structures for the responsive drug release from internal and external stimuli and to enhance the transdermal delivery efficiency for robust therapeutic outcomes. Some studies have proposed the use of drug-free MNs as a promising mechanotherapeutic strategy to promote wound healing, scar removal, and hair regeneration via a mechanical communication pathway. Although MNs have several advantages, the practical application of MNs suffers from problems related to industrial manufacture and clinical evaluation, making it difficult for clinical translation. In this study, we summarized the various applications, emerging challenges, and developmental prospects of MNs in skin disorders to provide information on ways to advance clinical translation.

Despite growing prevalence and incidence, the management of gout remains suboptimal. The intermittent nature of the gout makes the long-term urate-lowering therapy (ULT) particularly important for gout management. However, patients are reluctant to take medication day after day to manage incurable occasional gout flares, and suffer from possible long-term toxicity. Therefore, a safe and easy-to-operate drug delivery system with simple preparation for the long-term management of gout is very necessary. Here, a chitosan-containing sustained-release microneedle system co-loaded with colchicine and uricase liposomes were fabricated to achieve this goal. This microneedle system was confirmed to successfully deliver the drug to the skin and maintain a one-week drug retention. Furthermore, its powerful therapeutic potency to manage gout was investigated in both acute gouty and chronic gouty models. Besides, the drug co-delivery system could help avoid long-term daily oral colchicine, a drug with a narrow therapeutic index. This system also avoids mass injection of uricase by improving its stability, enhancing the clinical application value of uricase. In general, this two-drug system reduces the dosage of uricase and colchicine and improves the patient's compliance, which has a strong clinical translation.

Transdermal drug delivery systems (TDDs) avoid gastrointestinal degradation and hepatic first-pass metabolism, providing good drug bioavailability and patient compliance. One emerging type of TDDs is the wearable patch worn on the skin surface to deliver medication through the skin. They can generally be grouped into passive and active types, depending on the properties of materials, design principles and integrated devices. This review describes the latest advancement in the development of wearable patches, focusing on the integration of stimulus-responsive materials and electronics. This development is deemed to provide a dosage, temporal, and spatial control of therapeutics delivery.

Although vaccine administration by microneedles has been demonstrated, delivery reliability issues have prevented their implementation. Through an ex vivo porcine skin experiment, we show visual evidence indicating that detachable dissolvable microneedles (DDMN) can deposit cargo into the dermis with insignificant loss of cargo to the stratum corneum. Using ovalbumin (OVA), a model antigen vaccine, as a cargo, the ex vivo experiments yielded a delivery efficiency of 86.08 ± 4.16 %. At room temperature, OVA could be stabilized for up to 35 days in DDMN made from hyaluronic acid and trehalose. The DDMN matrix could improve the denaturation temperature of the OVA from around 70–120 °C to over 150 °C, as demonstrated by differential scanning calorimetric analysis. In vivo delivery of OVA antigen into the mice's skin via DDMN elicited 10 times higher specific antibody responses compared to conventional intramuscular injection. We envision DDMN as an effective, precise dosing, intradermal vaccine delivery system that may require no cold-chain, offers a dose-sparing effect, and can be administered easily.

Bone-related disorders treatment is a serious public health concern, imposing a significant social and economic burden on patients and healthcare systems. Although conventional drug delivery systems have made advances in bone diseases prevention and management, the limited delivery efficiency and convoluted focal environment lead to inadequate drug absorption and lack of specificity to achieve the intended therapeutic impact. Microneedle-based therapy represents an extraordinarily safe and well-tolerable therapeutic approach for treating bone disorders, providing improved efficacy by breaking down the barriers and delivery of therapeutic components to the target sites with programable release profiles in a less invasive manner. Over the past decades, numerous significant achievements in the development of various types of drug-carried microneedles have been made to address the obstacles encountered in the bone-treating procedure, enabling the microneedle-based therapy to take an important step in practical applications. In this light, this review summarizes these remarkable researches in terms of microneedles types and drug delivery strategies, with the goal of demonstrating the benefits of exploiting microneedle-based therapy as a novel strategy for treating bone-related disorders. The remaining challenges and future perspectives are also discussed in the hope of inspiring more efficient and intelligent bone treatment strategies.

The platform of microfluidics offers a precise control and manipulation over fluids at a small scale and therefore has gained much attention in recent times. This topic is currently applied to automation and high-throughput analysis in several areas, including extraction of DNA, RNA and proteins, gene identification, gene assembly, cloning, single-cell analysis, organs grown on chips, PCR, drug screening, toxicity testing and drug delivery. Conventional methods used for drug delivery are sometimes non-targeted leading to loss of administered drugs and reduced drug effectiveness. Recent advances in microfluidics allow precise dose-dependent delivery of a drug to a targeted location. Several microfluidics designs have been implemented to improve the precision of treatment in clinics. This review highlights currently available tools in microfluidics, designs for drug carriers, delivery methods, robotics and artificial intelligence in the field of microfluidics.

Androgenetic alopecia (AGA) is an androgen-mediated alopecia affected by both genes and hormones. Medication is a relatively common treatment. As a new drug delivery method, microneedles (MNs) can effectively break through the stratum corneum barrier, deliver drugs more efficiently, and achieve better therapeutic effects. In this study, we develop a composite double-layer MN through multi-step casting fabrication using a polydimethylsiloxane mold. The needle tip was fabricated by mixed solution of chitosan and polyvinylpyrrolidone which was loaded with Polygonum multiflorum extract, and the base layer was prepared by mixed solution of polyvinyl alcohol and polyvinylpyrrolidone. In vitro mechanical tests showed that the maximum load of a single tip of the drug-loaded MN was about 3.5 ​N, which met the mechanical requirements of skin puncture (>1 ​N). The drug release experiment showed that the MN could achieve gradual drug release. In the animal experiment, pigmentation and hair regrowth occurred earlier in the Polygonum multiflorum-MN (Pm-MN) group than in the other groups, and hair growth finally appeared in almost the entire area. Compared with the AGA model mice, mice in the Pm-MN group achieved an increase in the number and diameter of hair follicles. In conclusion, the Pm-MN is scientific and feasible for treating AGA.

Tissue injury is a common clinical problem, which may cause great burden on patients' life. It is important to develop functional scaffolds to promote tissue repair and regeneration. Due to their unique composition and structure, microneedles have attracted extensive attention in various tissues regeneration, including skin wound, corneal injury, myocardial infarction, endometrial injury, and spinal cord injury et al. Microneedles with micro-needle structure can effectively penetrate the barriers of necrotic tissue or biofilm, therefore improving the bioavailability of drugs. The use of microneedles to deliver bioactive molecules, mesenchymal stem cells, and growth factors in situ allows for targeted tissue and better spatial distribution. At the same time, microneedles can also provide mechanical support or directional traction for tissue, thus accelerating tissue repair. This review summarized the research progress of microneedles for in situ tissue regeneration over the past decade. At the same time, the shortcomings of existing researches, future research direction and clinical application prospect were also discussed.

The hair follicle is not only a critical penetration route in percutaneous absorption but also has been recognized to be a target for hair follicle-associated disorders, such as androgenetic alopecia (AGA) and acne vulgaris. Hair follicle-targeting drug delivery systems allow for controlled drug release and enhance therapeutic efficacy with minimal side effects, exerting a promising method for the management of hair follicle-associated dysfunctions. Therefore, they have obtained much attention in several fields of research in recent years. This review gives an overview of potential follicle-targeting drug delivery formulations currently applied based on the particularities of the hair follicles, including a comprehensive assessment of their preclinical and clinical performance.

Background: Skin cancer has been the leading type of cancer worldwide. Melanoma and non-melanoma skin cancers are now the most common types of skin cancer that have been reached to epidemic proportion. Based on the rapid prevalence of skin cancers, and lack of efficient drug delivery systems, it is essential to surge the possible ways to prevent or cure the disease. Aim of review: Although surgical modalities and therapies have been made great progress in recent years, however, there is still an urgent need to alleviate its increased burden. Hence, understanding the precise pathophysiological signaling mechanisms and all other factors of such skin insults will be beneficial for the development of more efficient therapies. Key scientific concepts of review: In this review, we explained new understandings about onset and development of skin cancer and described its management via polymeric micro/nano carriers-based therapies, highlighting the current key bottlenecks and future prospective in this field. In therapeutic drug/gene delivery approaches, polymeric carriers-based system is the most promising strategy. This review discusses that how polymers have successfully been exploited for development of micro/nanosized systems for efficient delivery of anticancer genes and drugs overcoming all the barriers and limitations associated with available conventional therapies. In addition to drug/gene delivery, intelligent polymeric nanocarriers platforms have also been established for combination anticancer therapies including photodynamic and photothermal, and for theranostic applications. This portfolio of latest approaches could promote the blooming growth of research and their clinical availability.

Parenteral sustained release drug formulations, acting as preferable platforms for long-term exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.

The repair of wounds is essential for overcoming injuries, but the process often leads to scars, and the formation mechanism is unclear. Interestingly, Bletilla striata polysaccharide (BSP) is a procoagulant and has anti-inflammatory properties to promote wound healing, which has great research value for scarless wound healing. Herein, we developed a transdermal drug delivery system of BSP/chitosan (CS) composite bilayer dissolvable microneedles (CS-AS-BSP MNs) containing asiaticoside (AS) based on a centrifugation method with a polydimethylsiloxane mould that fulfilled the requirements of wound healing and achieved a scar-free effect. The drug release results showed that this system improved the solubility of AS and maintained the stable release of the drug for a long time. Further experiments indicated that CS-AS-BSP MNs had a good antibacterial effect and reduced the proliferation of human scar fibroblasts. The wound healing effect of CS-AS-BSP MNs was evaluated in an experimental full-thickness-wound rat model, which demonstrated that the covered wound healed completely without scars within 3 weeks. Furthermore, CS-AS-BSP MNs downregulated TGF-β1 and COL Ⅰ, which are fibrosis-related genes, to inhibit scarring. In brief, this study provides a new strategy for meeting the clinical requirements of effective scarless wound dressings.

3-Acetylaconitine (AAC) is a natural compound with strong anti-inflammatory and analgesic properties, but the severely narrow safety range limited its clinical application. Two dissolvable microneedle (MN) systems, AAC-ORP-MN and AAC-MN, loaded with AAC liposomes (AAC-Lips) either mixed with or without Ostrea rivularis polysaccharide (ORP) were developed. The size, zeta potential and encapsulation efficiency of AAC-Lips were 112.9 ± 0.5 nm, -31.3 ± 0.5 mV and 95.7 ± 1.2 %. AAC-ORP-MN demonstrated higher mechanical strength and faster initial drug release rate compared to AAC-MN. The results in the spared nerve injury (SNI) model showed that AAC-ORP-MN and AAC-MN both could significantly increase the mechanical pain threshold on the operated side of the rats, and gradually decrease the difference between the equilibrium pain thresholds of both feet, but AAC-ORP-MN showed a faster onset of action. In addition, AAC-ORP-MN significantly reduced inflammatory factors and improved pathological damage in the spinal cord better than AAC-MN, which might be due to the anti-inflammatory activity of ORP. Overall, the above results supported that AAC-ORP-MN showed promise as a clinical option for analgesia, which had anti-inflammatory and analgesic properties, meanwhile it could effectively deliver poorly water-soluble AAC and improve its safety and availability., Competing Interests: Declaration of competing interest The authors state that they have no potential competing financial interests or personal relationships with other people or organizations that might unduly influence their work in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Effective monitoring of acetaminophen (APAP) dosage is crucial for preventing antipyretic abuse, ensuring therapeutic efficacy, and minimizing toxic effects. However, existing self-monitoring methods are limited. In this study, we designed a plasmonic microneedle (MN) sensor for real-time nondestructive monitoring of acetaminophen levels in dermal interstitial fluid (ISF) by employing a handheld Raman spectrometer. The fabricated MN sensor incorporated a high-density plasmonic MOFs known as HDPM, which unique structure of large specific surface area, specific pore structure as well as high density gold nanospheres packing enabled the excellent performance of selective ISF drug enrichment and surface-enhanced Raman scattering (SERS). The maximum electric field enhancement factor of the HDPM nanostructure could be calculated as 5.73 × 10 7 . The developed HDPM@MNs was characterized with a core-shell type "soft on the outside and rigid on the inside" structure, which exhibited sufficient hardness and flexibility to penetrate the dermal tissue with little damage, and robust SERS enhancement effect in APAP detection without any interfering peaks. Through a hydrogel drug simulation experiment, the sensor demonstrated robust capabilities for acetaminophen enrichment and monitoring, exhibiting excellent stability and repeatability. The quantitative detection window spanned from 1 to 100 μM, with a low detection limit reaching 0.45 μM. Furthermore, by monitoring the concentration of acetaminophen in the interstitial fluid of rat skin at different doses and for different administration times, the HDPM@MNs can be used to determine the pharmacokinetics of acetaminophen in rats and the physiological characteristics associated with various dosage regimens. This work not only holds promise for drug monitoring but also provides a novel approach for nondestructive monitoring of other crucial low-abundance physiological markers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To evaluate the efficacy of CO2 fractional laser and microneedling pretreatment combined with ALA-PDT for moderate-to-severe acne, aiming to optimize clinical treatment., Methods: Patients were randomly divided into three groups: Group A (CO2 fractional laser + ALA-PDT), Group B (microneedling + ALA-PDT), and Group C (ALA-PDT). Each group underwent photodynamic therapy once a week for 3 weeks. Efficacy was assessed at the end of the 4th week, and recurrence was assessed at the end of the 12th week., Results: A total of 150 patients with moderate to severe acne were included in this study, with 50 patients in each group. Four weeks after the end of treatment, the effective rates were 88 % for Group A, 62 % for Group B, and 36 % for Group C. Statistically significant differences were found between the groups (P < 0.05), with Group A showing superior efficacy compared to Group B (P < 0.05). No serious systemic or local adverse reactions were observed in any group. No recurrence was seen in any group 12 weeks after the end of treatment, and some patients continued to show improvement in skin lesions over time., Conclusion: Both the CO2 fractional laser group and the microneedling group improved the efficacy of photodynamic therapy for moderate to severe acne compared to the control group, with the CO2 fractional laser group demonstrating better efficacy and fewer adverse effects., (Copyright © 2024. Published by Elsevier B.V.)

With the public heightened emphasis on mitigating the occurrence risks of health-related ailment and optimizing personal physical performance, portable chemical sensing devices emerged as an indispensable component of pervasive health monitoring. Chemical sensing enabled the immediate and on-site identification of biomarkers in biological fluids by integrating colorimetry, fluorescence, electrochemical, and other methods into portable sensor devices. These sensor devices incorporated microneedles, hydrogels, microfluidic modules, and papers, facilitating conformal human-device contact and providing several visual sensing options for disease prevention and healthcare management. This review systematically overviewed recent advancements in chemical sensors for marker detection, categorizing them based on monitoring device types. Furthermore, we also offered recommendations and opportunities for developing portable chemical sensing devices by summarizing sensor integration methods and tracking sites on the human body., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Skin interstitial fluid (ISF) has emerged as a significant reservoir of biomarkers for disease diagnosis and prevention. Microneedle (MN) patches are regarded as an optimal platform for ISF extraction from the skin due to their non-invasive nature. However, challenges such as prolonged sampling durations and complex detection procedures impede timely metabolic analysis. In this investigation, we amalgamated MN technology with immobilized enzyme technology to fabricate a dual-layer MN patch integrating sampling and detection functionalities, thereby enabling in-situ colorimetric detection of hyperglycemia. The tip layer of the patch, comprising polyvinyl alcohol/carboxymethyl chitosan (PVA/CMCS) MN, was synthesized utilizing a chemical crosslinking approach for the first time, with glucose oxidase (GOx) being incorporated. The hydrophilicity of CMCS expedited the extraction process, facilitating the retrieval of approximately 10 mg of ISF within 10 min. The backing layer consisted of an immobilized polyvinyl alcohol-chitosan-horseradish peroxidase (PVA-CS-HRP) hydrogel film loaded with 3,3', 5,5'-tetramethylbenzidine (TMB). Incorporating macromolecular polymer PVA and CS for HRP immobilization addressed the issue of poor stability associated with traditional natural enzymes, thereby enhancing the sensitivity of the reaction system. The in-situ colorimetric sensor facilitated minimally invasive ISF extraction and swift conversion of glucose levels into detectable color changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Gouty arthritis (GA) is caused by monosodium urate (MSU) crystals deposition. GA is difficult to cure because of its complex disease mechanism and the tendency to reoccur. GA patients require long-term uric acid-lowering and anti-inflammatory treatments. In the past ten years, as a painless, convenient and well-tolerated new drug transdermal delivery method, microneedles (MNs) administration has been continuously developed, which can realize various drug release modes to deal with various complex diseases. Compared with the traditional administration methods (oral and injection), MNs are more conducive to the long-term independent treatment of GA patients because of their safe, efficient and controllable drug delivery ability. In this review, the pathological mechanism of GA and common therapeutic drugs for GA are summarized. After that, MNs drug delivery mechanisms were summarized: dissolution release mechanism, swelling release mechanism and channel-assisted release mechanism. According to drug delivery patterns of MNs, the mechanisms and applications of rapid-release MNs, long-acting MNs, intelligent-release MNs and multiple-release MNs were reviewed. Additionally, existing problems and future trends of MNs in the treatment of GA were also discussed. STATEMENT OF SIGNIFICANCE: Gout is an arthritis caused by metabolic disease "hyperuricemia". Epidemiological studies show that the number of gouty patients is increasing rapidly worldwide. Due to the complex disease mechanism and recurrent nature of gout, gouty patients require long-term therapy. However, traditional drug delivery modes (oral and injectable) have poor adherence, low drug utilization, and lack of local localized targeting. They may lead to adverse effects such as rashes and gastrointestinal reactions. As a painless, convenient and well-tolerated new drug transdermal delivery method, microneedles have been continuously developed, which can realize various drug release modes to deal with gouty arthritis. In this review, the material structure, design strategy and future outlook of microneedles for treating gouty arthritis will be reviewed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Currently, fungal and bacterial skin infections rank among the most challenging public health problems due to the increasing prevalence of microorganisms and the development of resistance to available drugs. A major issue in treating these infections with conventional topical medications is the poor penetration through the stratum corneum, the outermost layer of the skin. The concept of microneedles seems to be a future-proof approach for delivering drugs directly into deeper tissues. By bypassing the skin barrier, microneedle systems allow therapeutic substances to reach deeper layers more efficiently, significantly improving treatment outcomes. Nonetheless, the primary challenges regarding the effectiveness of microneedles involve selecting the appropriate size and shape, along with polymer composition and fabrication technology, to enable controlled and efficient drug release. This review offers a comprehensive overview of the latest knowledge on microneedle types and manufacturing techniques, highlighting their potential effectiveness in treating bacterial and fungal skin infections. It includes updated statistics on infection prevalence and provides a detailed examination of common bacterial and fungal diseases, focusing on their symptoms, causative species, and treatment methods. Additionally, the review addresses safety considerations, regulatory aspects, and future perspectives for microneedle-based therapeutic systems. It also underscores the importance of industrialization and clinical translation efforts, emphasizing the significant potential of microneedle technology for advancing medical applications., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chitosan (CS) has become a focal point of extensive research in the pharmaceutical industry due to its remarkable biodegradability, biocompatibility and sustainability. Chitosan hydrogels (CS HGs) are characterized by their viscoelasticity, flexibility and softness. The polar surfaces exhibit properties that mitigate interfacial tension between the hydrogel and body fluids. The inherent compatibility of CS HGs with body tissues and fluids positions them as outstanding polymers for delivering therapeutic proteins, peptides, DNA, siRNA, and vaccines. Designed to release drugs through mechanisms such as swelling-based diffusion, bioerosion, and responsiveness to stimuli, CS HGs offer a versatile platform for drug delivery. CS HGs play pivotal roles in serving purposes such as prolonging the duration of preprogrammed drug delivery, enabling stimuli-responsive smart delivery to target sites, protecting encapsulated drugs within the mesh network from adverse environments, and facilitating mucoadhesion and penetration through cell membranes. This review comprehensively outlines various novel preparation methods of CS HGs, delving into the parameters influencing drug delivery system design, providing a rationale for CS HG utilization in drug delivery, and presenting diverse applications across the pharmaceutical landscape. In synthesizing these facets, the review seeks to contribute to a nuanced understanding of the multifaceted role that CS HGs play in advancing drug delivery methodologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pain is a personalized event or body alarm system that can limit a patient's activities and lead to negative repercussions. The commercially available conventional treatment strategies like oral, parenteral, and topical drug delivery systems for pain management are associated with side effects and poor patient compliance. The transdermal route is eminent for its painless distribution. Among transdermal drug delivery system, microneedles (MNs) are gaining attention for their application with delivery at the deeper dermal layer because it bypasses the major barrier of the skin, easily accesses the skin dermal microcirculation, prevents damage to dermal blood vessels, and can be simply inserted into the skin without utilizing any additional applicator devices. Hence, considered a promising drug delivery strategy with high patient compliance. This review highlights the recent advancements of MNs in pain management. The present work mainly emphasizes all the case studies reported from the past 10 years that utilize MNs containing therapeutics in the treatment of chronic pain-associated diseases like rheumatoid arthritis, neuropathic pain, osteoarthritis, psoriatic arthritis, and atopic dermatitis. These studies have proven the efficacious application of MNs in the management of chronic pain and inflammation. The review also covered the clinical trials, patents, and future goals of pain management by using MNs.

Proteins and peptides have become a significant therapeutic modality for various diseases because of their high potency and specificity. However, the inherent properties of these drugs, such as large molecular weight, poor stability, and conformational flexibility, make them difficult to be formulated and delivered. Injection is the primary route for clinical administration of protein and peptide drugs, which usually leads to poor patient's compliance. As a portable, minimally invasive device, microneedles (MNs) can overcome the skin barrier and generate reversible microchannels for effective macromolecule permeation. In this review, we highlighted the recent advances in MNs-mediated transdermal delivery of protein and peptide drugs. Emphasis was given to the latest development in representative MNs design and fabrication. We also summarize the current application status of MNs-mediated transdermal protein and peptide delivery, especially in the field of infectious disease, diabetes, cancer, and other disease therapy. Finally, the current status of clinical translation and a perspective on future development are also provided.

Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of various types of cancer. However, even promising systemically administered ICB agents can cause immune-related adverse events (irAEs). The management of irAEs has been a significant concern. In addition to the risk of compromised immune function with corticosteroids and other immunomodulatory regimens used to treat irAEs, the complex mechanisms of irAEs make management of the “off-target” effects extremely challenging. Various materials with high biocompatibility, controllable degradability, and the ability for local and targeted delivery and controlled and sustained release of drugs have been explored to limit irAEs. Herein, we briefly review the fundamental mechanisms and clinical applications of immune checkpoint inhibitors and the potential mechanisms and clinical treatment of irAEs. We also highlight the application of emerging materials in the management of irAEs through “prevention” and “treatment”.

Hemangiomas are superficial tumors characterized by dense vascular structures that often affect the patient's aesthetic appearance due to the obvious red appearance on the skin. Current treatments, especially timolol maleate in the form of eye drops and hydrogels, suffer from low transdermal drug delivery rates, resulting in prolonged treatment time. To address this challenge, our study introduced a soluble microneedle patch with dextran as the main material to form microcatheters for sustained delivery of timolol maleate. In addition, we proposed a vascular embolization strategy to disrupt the blood supply in hemangiomas. Oxidized cellulose (C-cellulose) was selected for its excellent hemostatic properties. We incorporated C-cellulose into dextran microneedles to facilitate thrombosis in the vascular-rich areas of hemangiomas. The innovative microneedle patch we developed can penetrate the skin to a depth of 430 μm and dissolve rapidly within 3 minutes, ensuring direct drug delivery to the subcutaneous layer. Notably, the treated skin area regained its original appearance within two hours after treatment. In addition to excellent skin permeability and rapid dissolution, these patches significantly promoted apoptosis and inhibited cell migration in mouse hemangioendothelioma EOMA cells. Our results demonstrate that this approach not only achieves significant tumor inhibition in a mouse hemangioma model, but also represents a more effective, convenient, and non-invasive treatment option. Therefore, dextran/C-cellulose/timolol maleate microneedle patch (MNs/Timolol) has broad clinical application prospects in the treatment of hemangiomas, minimizing the risk of additional damage and improving treatment efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The human immunodeficiency virus (HIV) remains a global health concern, with 37.7 million people currently living with the infection and 1.5 million new cases every year. Current antiretroviral (ARV) therapies are administered through the oral route daily, often in lifelong treatments, leading to pill fatigue and poor treatment adherence. Therefore, the development of novel formulations for the administration ARV drugs using alternative routes is actively sought out. In this sense, microneedle array patches (MAPs) offer a unique user-centric platform that can be painlessly self-applied to the skin and deliver drugs to the systemic circulation. In this work, dissolving and implantable MAPs loaded with the tenofovir alafenamide (TAF) were developed with the aim of releasing the drug systemically. Both MAPs were sufficiently strong to pierce excised neonatal full-thickness porcine skin and form drug depots. In vitro release experiments performed in dialysis membrane models, demonstrated a relatively fast delivery of the drug in all cases. Franz cells experiments revealed that dissolving and implantable MAPs deposited 47.87 ​± ​16.33 ​μg and 1208.04 ​± ​417.9 ​μg of TAF in the skin after 24 ​h. Pharmacokinetic experiments in rats demonstrated a fast metabolization of TAF into tenofovir, with a rapid elimination of the metabolite from the plasma. The MAPs described in this work could be used as an alternative to current oral treatments for HIV management.

Transdermal drug delivery refers to the administration of drugs through the skin, after which the drugs can directly act on or circulate through the body to the target organs or cells and avoid the first-pass metabolism in the liver and kidneys experienced by oral drugs, reducing the risk of drug poisoning. From the initial singular approach to transdermal drug delivery, there has been a shift toward combining multiple methods to enhance drug permeation efficiency and address the limitations of individual approaches. Technological advancements have also improved the accuracy of drug delivery. Optimizing insulin itself also enables its long-term release via needle-free injectors. In this review, the diverse transdermal delivery methods employed in insulin therapy and their respective advantages and limitations are discussed. By considering factors such as the principles of transdermal penetration, drug delivery efficiency, research progress, synergistic innovations among different methods, patient compliance, skin damage, and posttreatment skin recovery, a comprehensive evaluation is presented, along with prospects for potential novel combinatorial approaches. Furthermore, as insulin is a macromolecular drug, insights gained from its transdermal delivery may also serve as a valuable reference for the use of other macromolecular drugs for treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This research transformed MTX into smart nanoparticles that respond to the acidic conditions present in inflammation. These nanoparticles were then incorporated into a patch that dissolves over time, aiding their penetration. A method using UV-Vis spectrophotometry was validated to support the development of this new delivery system. This method was used to measure the quantity of MTX in the prepared patches in various scenarios: in laboratory solutions with pH 7.4 and pH 5.0, in skin tissue, and plasma. This validation was conducted in laboratory studies, tissue samples, and live subjects, adhering to established guidelines. The resulting calibration curve displayed a linear relationship (correlation coefficient 0.999) across these scenarios. The lowest quantity of MTX that could be accurately detected was 0.6 µg/mL in pH 7.4 solutions, 1.46 µg/mL in pH 5.0 solutions, 1.11 µg/mL in skin tissue, and 1.48 µg/mL in plasma. This validated method exhibited precision and accuracy and was not influenced by dilution effects. The method was effectively used to measure MTX levels in the developed patch in controlled lab settings and biological systems (in vitro, ex vivo, and in vivo). This showed consistent drug content in the patches, controlled release patterns over 24 h, and pharmacokinetic profiles spanning 48 h. However, additional analytical approaches were necessary for quantifying MTX in studies focused on the drug's effects on the body's functions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The presence of bacterial biofilms in wounds is a main issue in the healing process. Conventional therapy of bacterial biofilms is hampered by the poor penetration of antibacterial agents through the physical barrier on the infected skin and the non-specific target of antibacterial agents. Here, we present a combination approach of bacterial sensitive nanoparticles (NPs) and dissolving microneedles (MNs) of doxycycline (DOX) for improved biofilm penetration and specifically delivering DOX to the infection site. The NPs were prepared from poly(lactic-co-glycolic acid) and poly (Ɛ-caprolactone) decorated with chitosan. The release of DOX was improved with the presence of bacterial producing biofilm up to 7-fold. The incorporation of these NPs into dissolving MNs was able to significantly enhance the dermatokinetic profiles of DOX, indicated by higher retention time compared to needle-free patches. Importantly, the antibiofilm activity in ex vivo biofilm model showed that after 48 h, the bacterial bioburdens decreased up to 99.99% following the application of this approach. The results presented here assist as proof of principle for the improvement of dermatokinetic profiles and antibiofilm activities of DOX, following its formulation into bacterial sensitive NPs and delivery via MN. Future studies must explore in vivo efficacy in a suitable animal model.

Intelligent wound management has important potential for promoting the recovery of chronic wounds caused by diabetes. Here, inspired by the field of kirigami, smart patterned high-stretch microneedle dressings (KPMDs) based on gene-modified spider silk proteins were developed to achieve sensitive biochemical and physiological sensing. The spider silk protein (spidroin) has excellent tensile properties, ductility, toughness and biocompatibility. Notably, the kirigami method-prepared kirigami structure of the spidroin MN dressing had a high tensile strength , while its ductility reached approximately 800 %. Moreover, the unique optical properties of photonic crystals allow for fluorescence enhancement, providing KPMD with color-sensitive properties suitable for wound management and clinical guidance. Furthermore, to improve the sensitivity of KPMD-s to motion monitoring, a microelectronic matrix was integrated on its surface. These distinct material properties suggest that this research lays the foundation for a new generation of high-performance biomimetic diatomaceous earth materials for application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic wounds are a common complication of diabetes. The prolonged exposure to high glucose and oxidative stress in the wound environment increases the risk of bacterial infection and abnormal angiogenesis, leading to amputation. Microneedle patches have shown promise in promoting the healing of diabetic wounds through transdermal drug delivery. These patches target the four main aspects of diabetic wound treatment: hypoglycemia, antibacterial action, inflammatory regulation, and tissue regeneration. By overcoming the limitations of traditional administration methods, microneedle patches enable targeted therapy for deteriorated tissues. The design of these patches extends beyond the selection of needle tip material and biomacromolecule encapsulated drugs; it can also incorporate near-infrared rays to facilitate cascade reactions and treat diabetic wounds. In this review, we comprehensively summarize the advantages of microneedle patches compared to traditional treatment methods. We focus on the design and mechanism of these patches based on existing experimental articles in the field and discuss the potential for future research on microneedle patches., Competing Interests: Declaration of competing interest All authors have disclosed any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. There is no use of any human and animal subjects in this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of a self-regulated minimally invasive system for insulin delivery can be considered as the holy grail in the field of diabetes mellitus. A delivery system capable of releasing insulin in response to blood glucose levels would significantly improve the quality of life of diabetic patients, eliminating the need for frequent finger-prick tests and providing better glycaemic control with lower risk of hypoglycaemia. In this context, the latest advances in glucose-responsive microneedle-based transdermal insulin delivery are here compiled with a thorough analysis of the delivery mechanisms and challenges lying ahead in their clinical translation. Two main groups of microneedle-based systems have been developed so far: glucose oxidase-containing and phenylboronic acid-containing systems. Both strategies in combination have also been tested and two other novel strategies are under development, namely electronic closed-loop and glucose transporter-based systems. Results from preclinical studies conducted using these different types of glucose-triggered release systems are comprehensively discussed. Altogether, this analysis from both a mechanistic and translational perspective will provide rationale and/or guidance for future trends in the research hotspot of glucose-responsive microneedle-based insulin delivery systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Microneedles are a promising micro-scale drug delivery platform that has been under development for over two decades. While 3D printing technology has been applied to fabricate these systems, the challenge of achieving needle sharpness remains. In this study, we present an innovative approach for microneedle fabrication using digital light processing (DLP) 3D printing and smart chitosan biomaterial. For the first time, we used hydroxybutyl methacrylated chitosan (HBCMA), which possesses dual temperature- and photo-sensitive properties, to create microneedles. The DLP approach enabled a quick generation of HBCMA-based microneedles with a high resolution. The microneedles exhibited 4D properties with a change in needle dimensions upon exposure to temperature, which enhances resolution, sharpens needles, and improves mechanical strength. We demonstrated the ability of these microneedles to load, deliver, sustained release small molecular drugs and penetrate soft tissue. Overall, the HBCMA-based microneedles show promising potential in non-dermal drug delivery applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, synthetic mRNA-based applications to produce desired exogenous proteins in cells have been gaining importance. However, systemic delivery of synthetic mRNA can result in unspecific uptake into undesired cells or organs and, thereby, fail to target desired cells. Thus, local and targeted delivery of synthetic mRNA becomes increasingly important to reach the desired cell types and tissues. In this study, intradermal delivery of synthetic mRNA using a hollow microneedle injection-based method was evaluated. Furthermore, an ex vivo porcine skin model was established to analyze synthetic mRNA-mediated protein expression in the skin following intradermal delivery. Using this model, highly efficient delivery of synthetic mRNA was demonstrated, which resulted in detection of high levels of secretable humanized Gaussia luciferase (hGLuc) protein encoded by the microinjected synthetic mRNA. Interestingly, synthetic mRNA injected without transfection reagent was also able to enter the cells and resulted in protein expression. The established ex vivo porcine skin model can be used to evaluate the successful production of desired proteins after intradermal delivery of synthetic mRNAs before starting with in vivo experiments. Furthermore, the use of microneedles enables patient-friendly, painless, and efficient delivery of synthetic mRNAs into the dermis; thus, this method could be applied for local treatment of different skin diseases as well as for vaccination and immunotherapy.

An ideal chronic wound dressing needs to have some properties, such as antibacterial, antioxidant, regulating macrophage polarization and promoting angiogenesis. This work presents a microneedle patch fabricated from oxidized konjac glucomannan (OKGM-MNs), in which Copper-gallate metal-organic framework (CuGA-MOF) is encapsulated for wound healing (denoted as CuGA-MOF@OKGM-MNs). CuGA-MOF is composed of Cu 2+ and gallic acid (GA), which are released through microneedles in the deep layer of the dermis. The released Cu 2+ is able to act as an antibacterial agent and promote angiogenesis, while GA as a reactive oxygen species scavenger displays antioxidant activity. More attractively, the material OKGM used to prepare the microneedle patch is not only a drug carrier but also plays a role in promoting macrophage polarization M2 phenotype. In vitro experiments showed that CuGA-MOF@OKGM-MNs had good antibacterial and antioxidant properties. The therapeutic effect on wound healing has been confirmed in full-thickness skin wounds of diabetes mice models, which showed that the wound could be completely healed within 21 days under the treatment of CuGA-MOF@OKGM-MNs, and the healing effect was better than other groups. These indicated that the proposed CuGA-MOF@OKGM-MNs could be applicable in the treatment of clinical wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Since it emerged in Brazil in May 2015, the mosquito-borne Zika virus (ZIKV) has raised global concern due to its association with a significant rise in the number of infants born with microcephaly and neurological disorders such as Guillain-Barré syndrome. We developed prototype subunit and adenoviral-based Zika vaccines encoding the extracellular portion of the ZIKV envelope gene (E) fused to the T4 fibritin foldon trimerization domain (Efl). The subunit vaccine was delivered intradermally through carboxymethyl cellulose microneedle array (MNA). The immunogenicity of these two vaccines, named Ad5.ZIKV-Efl and ZIKV-rEfl, was tested in C57BL/6 mice. Prime/boost immunization regimen was associated with induction of a ZIKV-specific antibody response, which provided neutralizing immunity. Moreover, protection was evaluated in seven-day-old pups after virulent ZIKV intraperitoneal challenge. Pups born to mice immunized with Ad5.ZIKV-Efl were all protected against lethal challenge infection without weight loss or neurological signs, while pups born to dams immunized with MNA-ZIKV-rEfl were partially protected (50%). No protection was seen in pups born to phosphate buffered saline-immunized mice. This study illustrates the preliminary efficacy of the E ZIKV antigen vaccination in controlling ZIKV infectivity, providing a promising candidate vaccine and antigen format for the prevention of Zika virus disease.

Triptolide (TP), a major active component of Tripterygium wilfordii Hook.F. (TWHF), is used to treat rheumatoid arthritis (RA). However, it has a narrow therapeutic window due to its serious toxicities. To increase the therapeutic index, a new triptolide-loaded transdermal delivery system, named triptolide-loaded liposome hydrogel patch (TP-LHP), has been developed. In this paper, we used a micro-needle array to deliver TP-LHP to promote transdermal absorption and evaluated this treatment on the pharmacokinetics and pharmacodynamics of TP-LHP in a rat model of collagen-induced arthritis (CIA). The pharmacokinetic results showed that transdermal delivery of microneedle TP-LHP yielded plasma drug levels which fit a one-compartment open model. The relationship equation between plasma concentration and time was C=303.59×(e−0.064t−e−0.287t). The results of pharmacodynamic study demonstrated that TP-LHP treatment mitigated the degree of joint swelling and suppressed the expressions of fetal liver kinase-1, fetal liver tyrosine kinase-4 and hypoxia-inducible factor-1α in synovium. Other indicators were also reduced by TP-LHP, including hyperfunction of immune, interleukin-1β and interleukin-6 levels in serum. The therapeutic mechanism of TP-LHP might be regulation of the balance between Th1 and Th2, as well as inhibition of the expression and biological effects of vascular endothelial growth factor.

There is an unmet need for a reliable and reproducible method for incorporating hair follicle derived stem cells in tissue engineered skin models to reconstitute hair follicles. This study discloses a novel method for introducing hair follicle derived stem cells in microneedle embossed micro-pits of a bilayer skin equivalent fabricated from a gelatin based scaffold. The microneedles are hard and strong enough to penetrate the upper layer of the bilayer gelatin based scaffold that corresponds to the epidermis and permeates down to lower layer that corresponds to dermal layer. This strategic location will mimic the natural niche of hair follicle stem cells for picking up signals from both the epidermis and dermis. Hair follicle stem cells are trapped in to these micro-pits by vacuum assisted cell seeding. The bilayer system consists of two distinct electrospun layers in a single processing step, representing outer epidermal layer and inner dermal layer with hair follicle stem cells in embedded pits, resulting in the formation of a closed representation of a complete skin., Competing Interests: Declaration of competing interest The authors declare that “There are no conflicts to declare”., (Copyright © 2023. Published by Elsevier B.V.)

Insulin aspart (IAsp) and insulin degludec (IDeg), as the third generation of insulin, have a faster onset time or a more durable action period, which may simulate the secretion of insulin under physiological conditions. Microneedles (MNs) are transdermal delivery devices that may allow diabetic patients to easily deploy transdermal insulin therapy while considerably reducing injection pain. In this study, we investigated the combination of dissolving MNs with IAsp or IDeg therapy as an alternative to daily multiple insulin injections, aiming to improve glycemic control and patient compliance. Mechanical properties of the MNs, structural stability of insulin encapsulated in the MNs, and transdermal application characteristics were studied to assess the practicality of insulin-loaded MNs for diabetes therapy. In vivo experiments conducted on diabetic rats demonstrated that the IAsp- and IDeg-loaded MNs have comparable blood glucose control abilities to that of subcutaneous injections. In addition, the therapeutic properties of insulin-loaded MNs under diverse dietary conditions and application strategies were further investigated to provide new information to support future clinical trials. Taken together, the proposed MNs have the potential to improve balances between glycemic control, hypoglycemia risk, and convenience, providing patients with simpler regimens. STATEMENT OF SIGNIFICANCE: 1. The fabricated functional insulin-loaded dissolving microneedles closely matched the glucose rise that occurs in response to meals, demonstrating promising alternatives for multiple daily insulin injections. 2. The hypoglycemic properties of insulin microneedles were investigated under diverse dietary conditions and application strategies, yielding new information to support future clinical trials. 3. Molecular dynamics simulations were utilized to study the interactions between the insulin and microneedle matrix materials, providing a strategy for theoretically understanding drug stability as well as the release mechanism of drug-loaded microneedles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA., Competing Interests: The authors declare no conflicts of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Topical 5-fluorouracil (5-FU) is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter). In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5%) was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy.

Despite growing prevalence and incidence, the management of gout remains suboptimal. The intermittent nature of the gout makes the long-term urate-lowering therapy (ULT) particularly important for gout management. However, patients are reluctant to take medication day after day to manage incurable occasional gout flares, and suffer from possible long-term toxicity. Therefore, a safe and easy-to-operate drug delivery system with simple preparation for the long-term management of gout is very necessary. Here, a chitosan-containing sustained-release microneedle system co-loaded with colchicine and uricase liposomes were fabricated to achieve this goal. This microneedle system was confirmed to successfully deliver the drug to the skin and maintain a one-week drug retention. Furthermore, its powerful therapeutic potency to manage gout was investigated in both acute gouty and chronic gouty models. Besides, the drug co-delivery system could help avoid long-term daily oral colchicine, a drug with a narrow therapeutic index. This system also avoids mass injection of uricase by improving its stability, enhancing the clinical application value of uricase. In general, this two-drug system reduces the dosage of uricase and colchicine and improves the patient's compliance, which has a strong clinical translation., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

To date, very limited work has been done on convenient and active control of insulin release. Herein, we report an electro-responsive insulin delivery system based on thiolated silk fibroin. The disulfide cross-linking points in TSF were reduced and broken to form sulfhydryl groups under electrification, which led to the increase of microneedle swelling degree and promoted insulin release. After power failure, the sulfhydryl group is oxidised to form disulfide bond crosslinking point again, resulting in the reduction of microneedle swelling degree and thus the reduction of release rate. The insulin loaded in the electro-responsive insulin delivery system showed good reversible electroresponsive release performance. The addition of graphene reduced the microneedle resistance and increased the drug release rate under current conditions. In vivo studies on type 1 diabetic mice show that electro-responsive insulin delivery system effectively controls the blood glucose before and after feeding by switching on and off the power supply, and this blood glucose control can be maintained within the safe range (100-200 mg/dL) for a long time (11h). Such electrically responsive delivery microneedles show potential for integration with glucose signal monitoring and are expected to build closed-loop insulin delivery systems., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Transdermal drug delivery systems (TDDs) avoid gastrointestinal degradation and hepatic first-pass metabolism, providing good drug bioavailability and patient compliance. One emerging type of TDDs is the wearable patch worn on the skin surface to deliver medication through the skin. They can generally be grouped into passive and active types, depending on the properties of materials, design principles and integrated devices. This review describes the latest advancement in the development of wearable patches, focusing on the integration of stimulus-responsive materials and electronics. This development is deemed to provide a dosage, temporal, and spatial control of therapeutics delivery., Competing Interests: The authors declare no conflicts of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)