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Atopic dermatitis (AD), a chronic and inflammatory skin disease, has brought huge physiological and psychological burdens to patients, which causes wide concerns in society. Herein, a multifunctional microneedle (MN) patch is proposed integrated with a desirable moisturizer and intelligent drug delivery capacity for AD treatment. Such MN patch consists of hyaluronic acid (HA) backing and near‐infrared (NIR) responsive tips containing black phosphorous quantum dots (BPQDs), low‐melting agarose, polyvinylpyrrolidone (PVP), and triamcinolone acetonide (TA). Among them, the soluble HA serves as a long‐term moisturizer for relieving dryness symptoms of AD. By introducing the NIR excitable and photothermal responsive BPQDs into agarose, the state of the composite material can be adjusted intelligently via NIR, thus achieving controllable release of the encapsulated TA in tips. Besides, PVP with enough mechanical strength can help MNs successfully penetrate the thickened skin of AD patients. Based on these advantages, it is demonstrated that the multifunctional MN patch reveals a satisfactory therapeutic effect in the AD model of Balb/c mice. These results indicate the potential values of the proposed MN patch in the treatment of AD skin diseases and other related biomedical fields. [ABSTRACT FROM AUTHOR]

Soft tissue injuries (STIs) are the most common cause of extremity pain and motion dysfunction. Persistent inflammatory activation of immune cells characterized by senescence‐associated secretory phenotype (SASP) and mitochondrial stress are considered the primary causes of STIs, a pathological process also termed inflammaging. Meanwhile, scavenging excessive "cellular waste" in the inflammaging microenvironment and further activating tissue repair processes remain elusive. Herein, an anti‐inflammaging photothermal hydrogel microneedle patch for treating STIs is developed. Taurine‐loaded Prussian blue nanoparticles (Taurine@PB) are encapsulated in a methacrylate‐based hyaluronic acid hydrogel (HAMA) and further fabricated into taurine@PB@HAMA@microneedles (TPH@MN) patches. The acidic microenvironment of chronic inflammation and mild photothermal effects promote taurine release and anti‐inflammaging immunomodulation, inhibiting mitochondrial stress via the SIRT3‐NF‐κB axis to promote glycolytic metabolic microenvironment of neutrophils reprogramming toward oxidative phosphorylation metabolism. Furthermore, TPH@MN activates macrophage efferocytosis and initiates the process of tissue repair. In mouse models of chronic diabetic wounds and tibialis anterior (TA) muscle injury, TPH@MN inhibits SASP expression and promotes STIs healing through thermosensitized anti‐inflammaging immunomodulation. In summary, TPH@MN circumvents the side effects of systemic administration, providing new translatable options in the treatment modalities for patients suffering from STIs worldwide. [ABSTRACT FROM AUTHOR]

Lurasidone, an antipsychotic medication for schizophrenia, is administered daily via oral intake. Adherence is a critical challenge, given that many schizophrenia patients deny their condition, thus making alternative delivery methods desirable. This study aimed to deliver lurasidone by the transdermal route and provide therapeutic effects for three days. Passive diffusion was found to be insufficient for lurasidone delivery. The addition of chemical enhancers increased permeation, but it was still insufficient to reach the designed target dose from a patch, so a microneedle patch array was fabricated by using biodegradable polymers. For prolonged and effective delivery, the drug was encapsulated in Poly (lactic-co-glycolic acid) (PLGA) nanoparticles which were made using the solvent evaporation method and incorporated in microneedles. Effervescent technology was also employed in the preparation of the microneedle patch to facilitate the separation of the needle tip from the patch. Once separated, only the needle tip remains embedded in the skin, thus preventing premature removal by the patient. The microneedles demonstrated robust preformation in a characterization test evaluating their insertion capacity, mechanical strength, and the uniformity of microneedle arrays, and were able to deliver a dose equivalent to 20 mg oral administration. Therefore, the potential of a transdermal delivery system for lurasidone using microneedles with nanoparticles was demonstrated. [ABSTRACT FROM AUTHOR]

Microneedle (MN) patches overcome the drawbacks associated with parenteral route (risk of needle-prick injury, costly supervised administration, production of biohazardous waste) and deliver vaccines transcutaneously into general circulation. This study aimed to summarise three case studies relating to MN patch mediated vaccine delivery. Bacillus Calmette–Guérin (BCG), tetanus toxoid (TT) and rabies vaccine loaded patches were prepared using sodium alginate (SA), polyvinyl pyrollidone (PVP)/carboxymethyl cellulose (CMC) and PVP/hyaluronic acid (HA), respectively. MNs were evaluated for morphology, folding endurance, swelling and insertion ability. In-vivo immunogenic activity was assessed by recording several parameters e.g., immunoglobulin G (IgG), interferon gamma (IFN-γ), T-cell (CD4+ and CD8+) and rabies virus specific antibody count following MN patch application. MNs, displaying sharp tips and uniform surface, showed a folding endurance and swelling of ≥200 and ~70%, respectively indicating integrity and fluid uptake ability. MNs successfully penetrated into the skin simulant parafilm. MNs treated groups exhibited a significant increase in the IgG, IFN-γ, CD4+, CD8+, rabies virus specific antibody counts when compared to the control (untreated) groups and the results were comparable with standard intramuscular injection. Thus, MN patches can be used for transcutaneous vaccine delivery.

Transdermal delivery of antigen and chemokine proteins that activates the maturation of skin dendritic cells (DCs) and direct the migration of activated DCs to lymph and spleen is an important alternative to conventional vaccines. However, stratum corneum forms a barrier to skin penetration. The poor cellular uptake of free antigens and chemokines also limits transcutaneous immunization efficacy. In this work, a pair of iontophoresis‐driven microneedle patches is constructed, of which, two kinds of outer membrane vesicles (OMVs) derived from Escherichia coli transformed by plasmid encoding gp100 (IPMN‐G) and chemokine ligand 21 (IPMN‐C) are incorporated within microneedles, respectively. The topical application of IPMN‐G and IPMN‐C shows the effectiveness of transdermally delivering gp100 and CCL21 secreting vesicles to skin DCs. With iontophoresis as a driving generator, the release and uptake of transgenic OMVs in target cells are significantly enhanced, with transcutaneous immunization initiated. The in vivo applications of IPMN‐G and IPMN‐C with a 12 h interval retard the progression and prevent the occurrence of tumor spheroids. IPMN‐GC is shown as a promising triplatform in engineering transgenic OMV‐incorporated microneedles, driven by iontophoresis into a transcutaneous vaccine, providing a noninvasive system for the transdermal delivery of antigen and chemokine proteins for transcutaneous vaccination‐meditated immunotherapy. [ABSTRACT FROM AUTHOR]

Fast dissolving microneedles (F-dMN) are quite a novel approach delivering specific drug molecules directly into the bloodstream, bypassing the first-pass effect. The present study reported an F-dMN patch to enhance systemic delivery of simvastatin in a patient-friendly manner. The F-dMN patch was developed using polyvinyl pyrrolidone and polyvinyl alcohol and characterized using light microscopy, SEM, XRD, FTIR, mechanical strength, drug content (%), an ex-vivo penetration study, an ex-vivo drug release study, a skin irritation test, and a pharmacokinetics study. The optimized F-dMN patch exhibited excellent elongation of 35.17%, good tensile strength of 9.68 MPa, an appropriate moisture content of 5.65%, and good penetrability up to 560 µm. Moreover, it showed 93.4% of the drug content within the needles and 81.75% in-vitro release. Histopathological findings and a skin irritation study proved that the F-dMN patch was biocompatible and did not cause any sort of irritation on animal skin. Pharmacokinetic parameters of F-dMN patches were improved (Cmax 6.974 µg/ml, tmax 1 hr and AUC 19. 518 µg.h/ml) as compared to tablet Simva 20 mg solution (Cmax 2.485 µg/ml, tmax 1.4 hr and AUC 11.199 µg.h/ml), thus confirming bioavailability enhancement. Moreover, stability studies confirmed the stability of the developed F-dMN patch, as investigated by axial needle fracture force and drug content. [ABSTRACT FROM AUTHOR]

[Display omitted] The biofilms formed by bacteria at the wound site can effectively protect the bacteria, which greatly weakens the effect of antibiotics. Herein, a microneedle patch for wound treatment is designed, which can effectively penetrate the biofilms in a physical way because of the penetration ability of the microneedles and the motion behavior of the nanomotors, and deliver bacterial quorum sensing inhibitor luteolin (Le) and nanomotors with multiple antibacterial properties within biofilms. Firstly, the nanomotors-loaded microneedle patches are prepared and characterized. The results of in vitro and in vivo experiments show that the microneedle patches have good biosafety and antibacterial properties. Among them, Le can inhibit the growth of biofilms. Further, under near-infrared (NIR) irradiation, the nanomotors loaded with photosensitizer ICG and nitric oxide (NO) donor L -arginine (L-Arg) can move in the biofilms under the double driving effect of photothermal and NO, and can give full play to the multiple anti-biological infection effects of photothermal therapy (PTT), photodynamic therapy (PDT) and NO, and finally realize the effective removal of biofilms and promote wound healing. The intervention of nanomotor technology has brought about a new therapeutic strategy for bacterial biofilm-related infection of wound. [ABSTRACT FROM AUTHOR]

Microneedle patches are promising transdermal drug delivery platforms with minimal invasiveness in a painless manner. Microneedle patch could be a promising alternate route for delivery of drugs having poor solubility and low bioavailability. This research work therefore, aimed to develop and characterize microneedle patch of thiolated chitosan (TCS) and polyvinyl acetate (PVA) for the systemic delivery of dydrogesterone (DYD). TCS-PVA-based microneedle patch was fabricated with 225 needles having a length of 575 µm with the sharp pointed end. Different ratios of TCS-PVA-based patch were employed to investigate the effects of mechanical tensile strength and percentage elongation. The scanning electron microscopy (SEM) revealed intact sharp-pointed needles. In vitro dissolution studies of microneedle patch (MN-P) were carried out by modified Franz-diffusion cell revealing the sustained release of DYD 81.45 ± 2.768 % at 48 hrs as compared to pure drug that showed 96.7 ± 1.75 % at 12 hrs. The transport of DYD (81%) across skin reaching the systemic circulation was evaluated through ex vivo permeation studies of MN-P. The skin penetration study through the parafilm M method showed good penetration with no deformation and breakage of needles along with no visible signs of skin irritation. Histological study of mice skins clearly showed the deeper penetration of needles into the skin. In summary, as-prepared MN-P show potential in developing an effective transdermal delivery system for DYD.

Hypertrophic scarring, an abnormal fibroproliferative wound‐healing disease, has brought tremendous burden for global healthcare systems. To date, no satisfactory treatment of hypertrophic scarring is available yet. Ferroptosis, an iron‐dependent form of cell death, has attracted much attention recently for the therapy of diseases featuring iron addiction. Intriguingly, myofibroblasts derived from hypertrophic scarring are found to exhibit a high iron state which appears to be sensitive to trigger ferroptosis for scarring treatment. Accordingly, in this study, a pH responsive self‐assembly nanoplatform is designed by encapsulating silver nanoclusters (AgNCs) and Chinese herbal medicine trigonelline (TRG) into zeolitic imidazolate framework‐8 (ZIF‐8) for synergistic ferroptosis therapy against hypertrophic scarring. The fabricated AgNC/TRG/ZIF‐8 composites exhibit good biocompatibility and pH responsive‐degradation inside myofibroblasts. The ZIF‐8 precursors can increase the generation of lipid reactive oxygen species and deplete intracellular glutathione (GSH). Also, AgNCs have the capability to consume GSH, while TRG can inhibit the activity of glutathione peroxidase. Consequently, the synergistic ferroptosis anti‐scarring therapy can be effectively achieved. Furthermore, AgNC/TRG/ZIF‐8‐loaded microneedle patches made of gelatin methacrylate show remarkable therapeutic effect against hypertrophic scarring on a rabbit ear model. This study suggests the great potential of ferroptosis‐mediated strategy for treating fibrotic skin diseases in future clinical application. [ABSTRACT FROM AUTHOR]

Microneedle patches are promising transdermal drug delivery platforms with minimal invasiveness in a painless manner. Microneedle patch could be a promising alternate route for delivery of drugs having poor solubility and low bioavailability. This research work therefore, aimed to develop and characterize microneedle patch of thiolated chitosan (TCS) and polyvinyl acetate (PVA) for the systemic delivery of dydrogesterone (DYD). TCS-PVA-based microneedle patch was fabricated with 225 needles having a length of 575 µm with the sharp pointed end. Different ratios of TCS-PVA-based patch were employed to investigate the effects of mechanical tensile strength and percentage elongation. The scanning electron microscopy (SEM) revealed intact sharp-pointed needles. In vitro dissolution studies of microneedle patch (MN-P) were carried out by modified Franz-diffusion cell revealing the sustained release of DYD 81.45 ± 2.768 % at 48 hrs as compared to pure drug that showed 96.7 ± 1.75 % at 12 hrs. The transport of DYD (81%) across skin reaching the systemic circulation was evaluated through ex vivo permeation studies of MN-P. The skin penetration study through the parafilm M method showed good penetration with no deformation and breakage of needles along with no visible signs of skin irritation. Histological study of mice skins clearly showed the deeper penetration of needles into the skin. In summary, as-prepared MN-P show potential in developing an effective transdermal delivery system for DYD. [ABSTRACT FROM AUTHOR]

Diabetes chronic wound is a severe and frequently occurring medical issue in patients with diabetes that often leads to more serious complications. Microneedles (MNs) can be used for wound healing as they can effectively pierce the epidermis and inject drugs into the wound tissue. However, common MN patches cannot provide sufficient skin adhesion to prevent detachment from the wound area. Inspired by the barb hangnail microstructure of porcupine quills, a porcupine quill-like multilayer MN patch with an adhesive back patching for tissue adhesion and diabetic wound healing was designed. Sodium hyaluronate-modified CaO 2 nanoparticles and metformin (hypoglycemic agent) were loaded into the polycaprolactone tips of MNs, endowing them with exceptional antibacterial ability and hypoglycemic effect. A flexible and adhesive back patching was formed by polyacrylamide-polydopamine/Cu2+ composite hydrogel, which ensures that the MN patches do not peel off from the application sites and reduce bacterial infection. The bioinspired multilayer structure of MN patches exhibits satisfactory mechanical and antibacterial properties, which is a potential multifunctional dressing platform for promoting wound healing. The porcupine quill-like microneedles (MNs) with PAM-PDA/Cu2+ (PPC) composite hydrogel back patching have been fabricated, which can enhance the adhesion property of MNs to the skin through a physical interlock of multilayer MNs and chemical bonding of hydrogel patching. CaO 2 -HA NPs and metformin were loaded into the polycaprolactone tips of MNs, endowing them with the exceptional antibacterial ability and hypoglycemic effect, which could accelerate diabetic wound healing. As a safe and effective strategy in transdermal delivery of drugs, the as-fabricated flexible multilayer MN patch with good antibacterial, hypoglycemic, and biocompatibility has been used to promote the healing of diabetic wound by releasing oxygen and inhibiting inflammation at the wound site. [Display omitted] [ABSTRACT FROM AUTHOR]

Benefiting from the advantages of minimal invasiveness, painlessness, and ease to use, microneedle patches (MPs) have been extensively studied in the biomedical field through a physical penetration enhancement pathway. This study systematically summarizes the preparation methods, function optimization, and diagnostic and therapeutic applications of MPs. First of all, the raw materials and methods commonly used in different preparation processes for MPs are highlighted. Then, the corresponding solutions to the problems facing MPs, such as poor tissue adhesion, weak mechanical strength, and low drug delivery utilization in their development and application, are emphasized, which serve as approaches to improve the performance of MPs. Subsequently, the latest applications of MPs for wound healing and health monitoring in recent years are summarized in‐depth, revealing the unique merits of MPs in diagnosis and treatment. Finally, the key points for the urgent improvement of MPs in clinical translation and commercial application are deliberated, in order to inspire the future direction of multifunctional and intelligent MPs.

Weak tissue adhesion remains a major challenge in clinical translation of microneedle patches. Mimicking the structural features of honeybee stingers, stiff polymeric microneedles with unidirectionally backward-facing barbs were fabricated and embedded into various elastomer films to produce self-interlocking microneedle patches. The spirality of the barbing pattern was adjusted to increase interlocking efficiency. In addition, the micro-bleeding caused by microneedle puncturing adhered the porous surface of the patch substrate to the target tissue via coagulation. In the demonstrative application of myocardial infarction treatment, the bioinspired microneedle patches firmly fixed on challenging beating hearts, significantly reduced cardiac wall stress and strain in the infarct, and maintained left ventricular function and morphology. In addition, the microneedle patch was minimally invasively implanted onto beating porcine heart in 10 minutes, free of sutures and adhesives. Therefore, the honeybee stinger-inspired microneedles could provide an adaptive and convenient means to implant patches for various medical applications. Adhesion between tissue and microneedle patches with smooth microneedles is usually weak. We introduce a novel barbing method of fabricating unidirectionally backward facing barbs with controllable spirality on the microneedles on microneedle patches. The microneedle patches self-interlock on mechanically dynamic beating hearts, similar to honeybee stingers. The micro-bleeding and coagulation on the porous surface provide additional adhesion force. The microneedle patches attenuate left ventricular remodeling via mechanical support and are compatible with minimally invasive implantation. [Display omitted] [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an emerging technique for treating tumors. Especially, topical administration of photosensitizers (PSs) is more favorable for superficial tumor treatments with low systematic phototoxicity. Yet, ineffective migration of PSs to targeted tumor tissues and rapid consumption of O2 during PDT greatly limit their effects. Herein, PS‐loaded microneedle (MN) patches with O2 propellant for a deeper and faster transdermal delivery of PS and improved PDT by embedding sodium percarbonate (SPC) into dissolving poly(vinyl pyrrolidone) MNs are presented. It is shown that SPC in the MNs can react with surrounding fluid to generate gaseous oxygen bubbles, forming vigorous fluid flows and thus greatly enhancing PS of chlorin e6 (Ce6) penetration in both hydrogel models and skin tissues. Reactive oxygen species (ROS) in hypoxic breast cancer cells (4T1 cells) are greatly increased by rapid penetration of PS and relief of hypoxia in vitro, and Ce6‐loaded SPC MNs show an excellent cell‐killing effect. Moreover, lower tumor growth rate and tumor mass after a 20‐d treatment in tumor‐bearing mice model verify the improved PDT in gaseous oxygen‐droved delivery of PS. This study demonstrates a facile yet effective route of MN delivery of PSs for improved PDT in hypoxic tumor treatment. [ABSTRACT FROM AUTHOR]

In the past decade, microneedle-based drug delivery systems showed promising approaches to become suitable and alternative for hypodermic injections and can control agent delivery without side effects compared to conventional approaches. Despite these advantages, the procedure of microfabrication is facing some difficulties. For instance, drug loading method, stability of drugs, and retention time are subjects of debate. Besides, the application of novel refining fabrication methods, types of materials, and instruments are other issues that need further attention. Herein, we tried to summarize recent achievements in controllable drug delivery systems (microneedle patches) in vitro and in vivo settings. In addition, we discussed the influence of delivered drugs on the cellular mechanism and immunization molecular signaling pathways through the intradermal delivery route. Understanding the putative efficiency of microneedle patches in human medicine can help us develop and design sophisticated therapeutic modalities. [ABSTRACT FROM AUTHOR]

In the past decade, microneedle-based drug delivery systems showed promising approaches to become suitable and alternative for hypodermic injections and can control agent delivery without side effects compared to conventional approaches. Despite these advantages, the procedure of microfabrication is facing some difficulties. For instance, drug loading method, stability of drugs, and retention time are subjects of debate. Besides, the application of novel refining fabrication methods, types of materials, and instruments are other issues that need further attention. Herein, we tried to summarize recent achievements in controllable drug delivery systems (microneedle patches) in vitro and in vivo settings. In addition, we discussed the influence of delivered drugs on the cellular mechanism and immunization molecular signaling pathways through the intradermal delivery route. Understanding the putative efficiency of microneedle patches in human medicine can help us develop and design sophisticated therapeutic modalities. [ABSTRACT FROM AUTHOR]

As microneedle (MN) patches progress towards commercialisation, there is a need to address issues surrounding their translation from the laboratory to the end-user. One important aspect of MN patches moving forward is appropriate primary packaging. This research focuses on MN patches containing amoxicillin (AMX) sodium for the potential treatment of neonatal sepsis in hot and humid countries. A MN patch consists of a hydrogel-forming MN array and a drug-containing reservoir. Improper primary packaging in hot and humid countries may result in degradation of active pharmaceutical ingredients, with the use of substandard medicines a major health concern. The research presented here, for the first time, seeks to investigate the integrity of MN patches in different primary packaging when stored under accelerated storage conditions, according to international guidelines. At pre-defined intervals, the performance of the MN patch was investigated. Major causes of drug instability are moisture and temperature. To avoid unnecessary degradation, suitable primary packaging was sought. After 168 days, the percentage of AMX sodium recovered from drug-containing reservoirs packaged in Protect™ 470 foil was 103.51 ± 7.03%. However, packaged in poly(ester) foil, the AMX sodium content decreased significantly (p = 0.0286), which is likely due to the degradation of AMX sodium by the imbibed moisture. Therefore, convincing evidence was provided as to the importance of investigating the stability of MN patches in primary packaging intended for MN-mediated transdermal delivery so that they are 'fit for purpose' when it reaches the end-user. Future work will include qualitative studies to assess MN patch usability. [ABSTRACT FROM AUTHOR]

[Display omitted] • A H 2 -realeasing MN patch realeases hydrogen at the deep site of diabetic wound continually. • Self-responsive H 2 -releasing microneedle patch accelerates diabetic wound healing by sequential action of H 2 and Co2+. • Sequential release of H 2 and Co2+ is achieved through the interaction of the microneedle and the backing. • An MN patch achieving integration and spatiotemporal control of antibacterial, ROS regulation, and proangiogenic functions. Oxidative stress regulation and synchronized promotion of angiogenesis are critical factors in the healing process of diabetic wounds. However, existing research often fails to fully consider the dynamic interplay between these two biological processes and their time-dependent roles in diabetic wound healing. This study innovatively introduces a novel hydrogen (H 2)-releasing microneedle patch capable of precisely controlling the regulation of oxidative stress and the promotion of angiogenesis through a bidirectional responsive mechanism of microneedles and backing layers. Specifically, we employ ammonia borane (AB)-loaded mesoporous silica nanoparticles (MSN) as a source of H 2 , combined with polyvinyl pyrrolidone (PVP) to fabricate microneedles. This design effectively clears excessive reactive oxygen species (ROS) in deep tissues and promotes the M2 polarization of macrophages. Concurrently, we utilize cobalt-adsorbed graphene oxide (GO/Co2+) mixed with polyvinyl alcohol (PVA) to prepare backing layers, which not only release Co2+ upon the reduction of oxygen-containing functional groups in GO by H 2 diffused from deep tissues to synergize with H 2 for enhanced vascularization, but also endow the microneedle patch with near-infrared (NIR) light-responsive antimicrobial properties, crucial for managing diabetic infected wounds. Through this innovative dual-action mechanism, our research significantly accelerates the healing process of infected wounds in a diabetic mouse model. Moreover, single-cell sequencing results further confirm the pivotal role of H 2 in regulating oxidative stress, promoting macrophage M2 polarization, and stimulating angiogenesis. These results not only showcase the unique features of our microneedle patch but also offer new perspectives and therapeutic strategies for the treatment of diabetic wounds. [ABSTRACT FROM AUTHOR]

Aoife M Rodgers, Ana Sara Cordeiro, Ryan F Donnelly School of Pharmacy, Queen’s University Belfast, Belfast, BT9 7BL, UKCorrespondence: Ryan F DonnellySchool of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UKTel +44 289 097 2251Fax +44 289 024 7794Email r.donnelly@qub.ac.ukAbstract: Despite vaccination representing one of the greatest advances of modern preventative medicine, there remain significant challenges in vaccine distribution, delivery and compliance. Dissolvable microarray patches or dissolving microneedles (DMN) have been proposed as an innovative vaccine delivery platform that could potentially revolutionize vaccine delivery and circumvent many of the challenges faced with current vaccine strategies. DMN, due to their ease of use, lack of elicitation of pain response, self-disabling nature and ease of transport and distribution, offer an attractive delivery option for vaccines. Additionally, as DMN inherently targets the uppermost skin layers, they facilitate improved vaccine efficacy, due to direct targeting of skin antigen-presenting cells. A plethora of publications have demonstrated the efficacy of DMN vaccination for a range of vaccines, with influenza receiving particular attention. However, before the viable adoption of DMN for vaccination purposes in a clinical setting, a number of fundamental questions must be addressed. Accordingly, this review begins by introducing some of the key barriers faced by current vaccination approaches and how DMN can overcome these challenges. We introduce some of the recent advances in the field of DMN technology, highlighting the potential impact DMN could have, particularly in countries of the developing world. We conclude by reflecting on some of the key questions that remain unanswered and which warrant further investigation before DMNs can be utilized in clinical settings.Keywords: microneedle patches, dissolvable, vaccine, cold chain, hazardous sharps waste, skin

The transdermal drug delivery system is an exceptionally safe and well-tolerable therapeutic approach that has immense potential for delivering active components against bone-related pathologies. However, its use is limited in the current clinical practices due to the low skin permeability of most active drugs in the formulation. Thus, innovations in the methodologies of skin permeation enhancement techniques are suggested to overcome this limitation. Although various transdermal drug delivery systems are studied to date, there are insufficient studies comparing the therapeutic efficacy of transdermal delivery systems to oral delivery systems. Thus, creating a decision-making dilemma between oral or transdermal therapies. Therefore, a timely review is inevitable to develop a platform for future researchers to develop next-generation transdermal drug delivery strategies against skeletal diseases that must be convenient and cost-effective for the patients with improved therapeutic efficacy. Here, we will outline the most recent strategies that can overcome the choice limitation of the drug and enhance the transdermal adsorption of various types of drugs to treat bone disorders. For the first time, in this review paper, we will highlight the preclinical and clinical studies on the different transdermal delivery methods. Thus, providing insight into the current therapeutic approaches and suggesting new directions for the advancements in transdermal drug delivery systems against bone disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood-brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ's efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.

Wearable epidermal electronics with non- or minimally-invasive characteristics can collect, transduce, communicate, and interact with accessible physicochemical health indicators on the skin. However, due to the stratum corneum layer, rich information about body health is buried under the skin stratum corneum layer, for example, in the skin interstitial fluid. Microneedle patches are typically designed with arrays of special microsized needles of length within 1000 µm. Such characteristics potentially enable the access and sample of biomolecules under the skin or give therapeutical treatment painlessly and transdermally. Integrating microneedle patches with various electronics allows highly efficient transdermal bioelectronics, showing their great promise for biomedical and healthcare applications. This comprehensive review summarizes and highlights the recent progress on integrated transdermal bioelectronics based on microneedle patches. The design criteria and state-of-the-art fabrication techniques for such devices are initially discussed. Next, devices with different functions, including but not limited to health monitoring, drug delivery, and therapeutical treatment, are highlighted in detail. Finally, key issues associated with current technologies and future opportunities are elaborated to sort out the state of recent research, point out potential bottlenecks, and provide future research directions., (© 2024 Wiley‐VCH GmbH.)

The aim of this study was to fabricate Bacillus Calmette–Guérin (BCG)-loaded microneedle patches using micromould casting technique and compare their efficacy with the injectable counterparts. The microneedle patches were formulated using sodium alginate (10% w/v) and trehalose (20% of polymer). The patches were characterised using optical microscopy, scanning electron microscopy and folding endurance. Serum IgG, TLC, granulocyte count, lymphocyte count and CRP were assessed and results were compared to that of intradermal injections alongside controls. The results showed that polymeric patches had a thickness of 0.8 mm, microneedle projections of 272 ± 12 µm and folding endurance of more than 300. Based on haematological and IgG ELISA assays, microneedle-based BCG administration significantly activated the immune cells and induced production of lymphocytes, granulocytes and peptide-specific IgG in immunised rats that were comparable to injectable counterparts. There was an increase in IgG antibodies from 3 g/L to 5.98 g/L and an increase in leucocytes from 2.6 × 109/L to 18.45 × 109/L. There was also an increase in granulocytes from 14.4% to 29.15% and lymphocyte count from 58.75% to 85.3%. It was concluded that BCG-coated polymeric microneedle patches are suitable for the transdermal delivery of vaccine without inducing discomfort usually observed with injections. [ABSTRACT FROM AUTHOR]

Wounds and the subsequent formation of scars constitute a unified and complex phased process. Effective treatment is crucial; however, the diverse therapeutic approaches for different wounds and scars, as well as varying treatment needs at different stages, present significant challenges in selecting appropriate interventions. Microneedle patch (MNP), as a novel minimally invasive transdermal drug delivery system, has the potential for integrated and programmed treatment of various diseases and has shown promising applications in different types of wounds and scars. In this comprehensive review, the latest applications and biotechnological innovations of MNPs in these fields are thoroughly explored, summarizing their powerful abilities to accelerate healing, inhibit scar formation, and manage related symptoms. Moreover, potential applications in various scenarios are discussed. Additionally, the side effects, manufacturing processes, and material selection to explore the clinical translational potential are investigated. This groundwork can provide a theoretical basis and serve as a catalyst for future innovations in the pursuit of favorable therapeutic options for skin tissue regeneration., (© 2023 Wiley‐VCH GmbH.)

Microarray patches (MAPs), also referred to as microneedle patches, are a novel methodology that have the potential to overcome barriers to vaccine delivery in low- and middle-income countries (LMICs), and transform the way that vaccines are delivered within immunization programs. The World Health Organization's Initiative for Vaccine Research and its partners are working to understand how MAPs could ease vaccine delivery and increase equitable access to vaccines in LMICs. Global stakeholders have been engaged to evaluate technical, economic, and programmatic challenges; to validate assumptions where possible; and to propose areas of focus to facilitate future vaccine-MAP product development. This report summarizes those learnings. [ABSTRACT FROM AUTHOR]

The microneedle (MN), a highly efficient and versatile device, has attracted extensive scientific and industrial interests in the past decades due to prominent properties including painless penetration, low cost, excellent therapeutic efficacy, and relative safety. The robust microneedle enabling transdermal delivery has a paramount potential to create advanced functional devices with superior nature for biomedical applications. In this review, a great effort has been made to summarize the advance of microneedles including their materials and latest fabrication method, such as three-dimensional printing (3DP). Importantly, a variety of representative biomedical applications of microneedles such as disease treatment, immunobiological administration, disease diagnosis and cosmetic field, are highlighted in detail. At last, conclusions and future perspectives for development of advanced microneedles in biomedical fields have been discussed systematically. Taken together, as an emerging tool, microneedles have showed profound promise for biomedical applications. As a promising device, microneedles have made significant progress for revolutionizing the field of disease treatment, immunobiological administration, disease diagnosis, and cosmetic applications. We discuss a variety of materials and fabrication methods of microneedles. The conclusions and future perspectives for development of advanced microneedles in biomedical application are addressed. Image 1 [ABSTRACT FROM AUTHOR]

Wound healing is a well-orchestrated progress associated with angiogenesis, epithelialization, inflammatory status, and infection control, whereas these processes are seriously disturbed in diabetic wounds. In this study, a biohybrid dressing integrating the inherent ability of Bromeliad leaf (photosynthesis and self-draining) with the therapeutic effect of artificial materials (glucose-degrading and ROS-scavenging) is presented. The dressing consists of double-layered structures as follows: 1) Outer layer, a Bromeliad leaf substrate full of alginate hydrogel-immobilized glucose oxidase (GOx@Alg@Bromeliad substrate, abbreviated as BGA), can generate oxygen to guarantee the GOx-catalyzed glucose oxidation by photosynthesis, reducing local hyperglycemia to stabilize hypoxia inducible factor-1 alpha (HIF-1α) for angiogenesis and producing hydrogen peroxide for killing bacteria on the surface of wound tissue. The sophisticated structure of the leaf drains excessive exudate away via transpiration-mimicking, preventing skin maceration and impeding bacterial growth. 2) Inner layer, microneedles containing catalase (CAT-HA MNs, abbreviated as CHM), reduces excessive oxidative stress in the tissue to promote the proliferation of fibroblasts and inhibits proinflammatory polarization of macrophages, improving re-epithelialization of diabetic wounds. Together, the biohybrid dressing (BGA-CHM, abbreviated as BCHM) can enhance angiogenesis, strengthen re-epithelialization, alleviate chronic inflammation, and suppress bacterial infection, providing a promising strategy for diabetic wound therapy., (© 2023 Wiley-VCH GmbH.)

Peripheral nerve defects, particularly those of a larger size, pose a significant challenge in clinical practice due to their limited regenerative capacity. To tackle this challenge, an advanced self-powered enzyme-linked microneedle (MN) nerve conduit is designed and fabricated. This innovative conduit is composed of anodic and cathodic MN arrays, which contain glucose oxidase (GOx) and horseradish peroxidase (HRP) encapsulated in ZIF-8 nanoparticles, respectively. Through an enzymatic cascade reaction, this MN nerve conduit generates microcurrents that stimulate the regeneration of muscles, blood vessels, and nerve fibers innervated by the sciatic nerve, eventually accelerating the repair of sciatic nerve injury. It is clear that this self-powered MN nerve conduit will revolutionize traditional treatment methods for sciatic nerve injury and find widespread application in the field of nerve tissue repair., (© 2023 Wiley-VCH GmbH.)

Additive manufacturing, commonly known as 3D printing, allows decentralized drug fabrication of orally administered tablets. Microneedles are comparatively favorable for self-administered transdermal drug delivery with improved absorption and bioavailability. Due to the cross-scale geometric characteristics, 3D-printed microneedles face a significant trade-off between the feature resolution and production speed in conventional layer-wise deposition sequences. In this study, we introduce an economical and scalable direct ink drawing strategy to create drug-loaded microneedles. A freestanding microneedle is efficiently generated upon each pneumatic extrusion and controlled drawing process. Sharp tips of ∼5 μm are formed with submillimeter nozzles, representing 2 orders of magnitude improved resolution. As the key enabler of this fabrication strategy, the yield-stress fluid inks are formulated by simply filling silica nanoparticles into regular polymer solutions. The approach is compatible with various microneedles based on dissolvable, biodegradable, and nondegradable polymers. Various matrices are readily adopted to adjust the release behaviors of the drug-loaded microneedles. Successful fabrication of multifunctional patches with heterogeneously integrated microneedles allows the treatment of melanoma via synergistic photothermal therapy and combination chemotherapy. The personalized patches are designed for cancer severity to achieve high therapeutic efficacy with minimal side effects. The direct ink drawing reported here provides a facile and low-cost fabrication strategy for multifunctional microneedle patches for self-administering transdermal drug delivery.

Microneedle (MN) patches, which allow the extraction of skin interstitial fluid (ISF) without a pain sensation, are powerful tools for minimally invasive biofluid sampling. Herein, an MN-assisted paper-based sensing platform that enables rapid and painless biofluid analysis with ultrasensitive molecular recognition capacity is developed. First, a controllable-swelling MN patch is constructed through the engineering of a poly(ethylene glycol) diacrylate/methacrylated hyaluronic acid hydrogel; it combines rapid, sufficient extraction of ISF with excellent structural integrity. Notably, the analyte molecules in the needles can be recovered into a moist cellulose paper through spontaneous diffusion. More importantly, the paper can be functionalized with enzymatic colorimetric reagents or a plasmonic array, enabling a desired detection capacity-for example, the use of paper-based surface-enhanced Raman spectroscopy sensors leads to label-free, trace detection (sub-ppb level) of a diverse set of molecules (cefazolin, nicotine, paraquat, methylene blue). Finally, nicotine is selected as a model drug to evaluate the painless monitoring of three human volunteers. The changes in the nicotine levels can be tracked, with the levels varying significantly in response to the metabolism of drug in different volunteers. This as-designed minimally invasive sensing system should open up new opportunities for precision medicine, especially for personal healthcare monitoring., (© 2023 Wiley-VCH GmbH.)

Chronic nonhealing diabetic wounds are becoming increasingly severe, with high rates of mortality and disability, owing to the difficulty in wound healing caused by hyperglycemia, blocked angiogenesis, biofilm infection, and excessive oxidative stress. A multicomponent enzyme-responsive natural polymer, a hyaluronic acid (HA) microneedle, embedded in a cerium/zinc-based nanomaterial (ZCO) for the treatment of diabetic wounds is reported. ZCO-HA can destroy the oxidation balance of bacteria, kill bacteria, and scavenge reactive oxygen species (ROS) to alleviate oxidative stress via the adjustable release of Zn 2+ and Ce 3+ / 4+ . Additionally, ZCO-HA exhibits good anti-inflammatory activity through the nuclear factor kappa-B (NF-κB) pathway, which reduces the inflammatory state of macrophages and promotes cell proliferation, migration, and angiogenesis. In vitro experiments shows that ZCO-HA accompanies mouse fibroblast migration, promoting human umbilical vein endothelial cell tube formation. In vivo studies in mice with streptozotocin-induced (STZ)-induced diabetes reveal that this microneedle accelerates wound healing without systemic toxicity. RNA transcriptome sequencing illustrates that the multicomponent HA microneedle accelerates wound healing in diabetes through cell migration and inhibits inflammatory reactions and oxidative damage in mice via the NF-κB signaling pathway., (© 2023 Wiley-VCH GmbH.)

Bioprinting has attracted much attention due to its suitability for fabricating biomedical devices. In particular, bioprinting has become one of the growing centers in the field of wound healing, with various types of bioprinted devices being developed, including 3D scaffolds, microneedle patches, and flexible electronics. Bioprinted devices can be designed with specific biostructures and biofunctions that closely match the shape of wound sites and accelerate the regeneration of skin through various approaches. Herein, a comprehensive review of the bioprinting of smart wound dressings is presented, emphasizing the crucial effect of bioprinting in determining biostructures and biofunctions. The review begins with an overview of bioprinting techniques and bioprinted devices, followed with an in-depth discussion of polymer-based inks, modification strategies, additive ingredients, properties, and applications. The strategies for the modification of bioprinted devices are divided into seven categories, including chemical synthesis of novel inks, physical blending, coaxial bioprinting, multimaterial bioprinting, physical absorption, chemical immobilization, and hybridization with living cells, and examples are presented. Thereafter, the frontiers of bioprinting and wound healing, including 4D bioprinting, artificial intelligence-assisted bioprinting, and in situ bioprinting, are discussed from a perspective of interdisciplinary sciences. Finally, the current challenges and future prospects in this field are highlighted., (© 2023 Wiley-VCH GmbH.)

Exploration of clinically acceptable blood glucose monitors has been engaging in the past decades, yet the ability to quantitatively detect blood glucose in a painless, accurate, and highly sensitive manner remains limited. Herein, a fluorescence-amplified origami microneedle (FAOM) device is described that integrates tubular DNA-origami nanostructures and glucose oxidase molecules into its inner network to quantitatively monitor blood glucose. The skin-attached FAOM device can collect glucose molecules in situ and transfer the input into a proton signal after the oxidase's catalysis. The proton-driven mechanical reconfiguration of DNA-origami tubes separates fluorescent molecules and their quenchers, eventually amplifying the glucose-correlated fluorescence signal. The function equation established on clinical examinees suggests that FAOM can report blood glucose in a highly sensitive and quantitative manner. In clinical blind tests, the FAOM achieves well-matched accuracy (98.70 ± 4.77%) compared with a commercial blood biochemical analyzer, fully meeting the requirements of accurate blood glucose monitoring. The FAOM device can be inserted into skin tissue in a trivially painful manner and with minimal leakage of DNA origami, substantially improving the tolerance and compliance of the blood glucose test., (© 2023 Wiley-VCH GmbH.)

Myocardial infarction (MI) is a cardiovascular disease that poses a serious threat to human health. Uncontrolled and excessive cardiac fibrosis after MI has been recognized as a primary contributor to mortality by heart failure. Thus, prevention of fibrosis or alleviation of fibrosis progression is important for cardiac repair. To this end, a biocompatible microneedle (MN) patch based on gelatin is fabricated to load exosomes containing microRNA-29b (miR-29b) mimics with antifibrotic activity to prevent excessive cardiac fibrosis after MI. Exosomes are isolated from human umbilical cord mesenchymal stem cells and loaded with miR-29b mimics via electroporation, which can be internalized effectively in cardiac fibroblasts to upregulate the expression of miR-29b and downregulate the expression of fibrosis-related proteins. After being implanted in the infarcted heart of a mouse MI model, the MN patch can increase the retention of loaded exosomes in the infarcted myocardium, leading to alleviation of inflammation, reduction of the infarct size, inhibition of fibrosis, and improvement of cardiac function. This design explored the MN patch as a suitable platform to deliver exosomes containing antifibrotic biomolecules locally for the prevention of cardiac fibrosis, showing the potential for MI treatment in clinical applications., (© 2023 Wiley-VCH GmbH.)

Introduction: There is a need for investment in manufacturing for vaccine microarray patches (vMAPs) to accelerate vMAP development and access. vMAPs could transform vaccines deployment and reach to everyone, everywhere., Areas Covered: We outline vMAPs' potential benefits for epidemic preparedness and for outreach in low- and lower-middle-income countries (LMICs), share lessons learned from pandemic response, and highlight that investment in manufacturing-at-risk could accelerate vMAP development., Expert Opinion: Pilot manufacturing capabilities are needed to produce clinical trial material and enable emergency response. Funding vMAP manufacturing scale-up in parallel to clinical proof-of-concept studies could accelerate vMAP approval and availability. Incentives could mitigate the risks of establishing multi-vMAP manufacturing facilities early.

A composite microneedle patch (MN patch) is developed for oral transmucosal administration. To improve the oral transmucosal drug delivery efficiency, the composite MN patch is designed to consist of an array of 100 dissolvable microneedles (MNs) with drug-loaded tips and a backing layer. The MNs are composed of two parts, the hyaluronic acid (HA) tip part and the polyvinylpyrrolidone (PVP) base part. Due to the small size and sufficient mechanical strength, the HA-PVP MNs can painlessly penetrate the oral mucosa barrier and deliver drugs directly to the basal layer or submucosa. Betamethasone sodium phosphate (BSP), as the model drug, is concentrated in the HA tip parts to avoid the drug waste caused by mucosa elasticity. Considering the special moist environment and saliva flow in the mouth, a double-layer backing layer composed of a poly(vinyl alcohol) (PVA) adhesive layer and an ethyl cellulose (EC) waterproof layer is designed and constructed, which could reduce the saliva flow effects. The in vitro and in vivo results demonstrate that the MN patch could achieve rapid and efficient BSP release in oral mucosa due to the rapid dissolution of HA. The proposed MN patch provides a novel strategy for the therapy of oral mucosal diseases., (Copyright © 2022. Published by Elsevier B.V.)

In this study, a first attempt has been made to deliver levosulpiride transdermally through a thiolated chitosan microneedle patch (TC-MNP). Levosulpiride is slowly and weakly absorbed from the gastrointestinal tract with an oral bioavailability of less than 25% and short half-life of about 6 h. In order to enhance its bioavailability, levosulpiride-loaded thiolated chitosan microneedle patches (LS-TC-MNPs) were fabricated. Firstly, thiolated chitosan was synthesized and characterized by nuclear magnetic resonance (1HNMR) spectroscopy, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Thiolated chitosan has been used in different drug delivery systems; herein, thiolated chitosan has been used for the transdermal delivery of LS. LS-TC-MNPs were fabricated from different concentrations of thiolated chitosan solution. Furthermore, the levosulpiride-loaded thiolated chitosan microneedle patch (LS-TC-MNP) was characterized by FTIR spectroscopic analysis, scanning electron microscopy (SEM) study, penetration ability, tensile strength, moisture content, patch thickness, and elongation test. LS-TC-MNP fabricated with 3% thiolated chitosan solution was found to have the best tensile strength, moisture content, patch thickness, elongation, drug-loading efficiency, and drug content. Thiolated chitosan is biodegradable, nontoxic and has good absorption and swelling in the skin. LS-TC-MNP-3 consists of 100 needles in 10 rows each with 10 needles. The length of each microneedle was 575 μm; they were pyramidal in shape, with sharp pointed ends and a base diameter of 200 µm. The microneedle patch (LS-TC-MNP-3) resulted in-vitro drug release of 65% up to 48 h, ex vivo permeation of 63.6%, with good skin biocompatibility and enhanced in-vivo pharmacokinetics (AUC = 986 µg/mL·h, Cmax = 24.5 µg/mL) as compared to oral LS dispersion (AUC = 3.2 µg/mL·h, Cmax = 0.5 µg/mL). Based on the above results, LS-TC-MNP-3 seems to be a promising strategy for enhancing the bioavailability of levosulpiride. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Surgery followed by chemotherapy and radiotherapy remains the standard treatment strategy for GBM patients. However, challenges still exist when surgery is difficult or impossible to remove the tumor completely. Herein, the design, fabrication and application of a heterogenous silk fibroin microneedle (SMN) patch is reported for circumventing the blood-brain barrier and releasing multiple drugs directly to the tumor site for drug combination treatment. The biocompatible and biodegradable SMN patch can dissolve slowly over time, allowing the sustained release of multiple drugs at different doses. Furthermore, it can be triggered remotely to induce rapid drug delivery at a designated stage after implantation. In the GBM mouse models, two clinically relevant chemotherapeutic agents (thrombin and temozolomide) and targeted drug (bevacizumab) are loaded into the SMN patch with individually controlled release profiles. The drugs are spatiotemporally and sequentially delivered for hemostasis, anti-angiogenesis, and apoptosis of tumor cells. Device application is non-toxic and results in decreased tumor volume and increased survival rate in mice. The SMN patch with on-demand multidrug delivery has potential applications for the combined administration of therapeutic drugs for the clinical treatment of brain tumors when other methods are insufficient., (© 2021 Wiley-VCH GmbH.)

• Long-acting injectable or implantable antiretrovirals are an alternative to oral drugs. • Long-acting cabotegravir and rilpivirine should be approved shortly. • Extended-release polymer implants are in development. • Transcutaneous microarray patches are a novel drug delivery system. Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long-acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early- and late-stage clinical trials. Strategies to manage toxicity and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated and efficacious in large randomised phase 3 studies. Regulatory approval for this two-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the USA during 2021. 4ʹ-Ethynyl-2-fluoro-2′-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long-acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly-neutralising monoclonal antibodies have potent antiviral activity in early human trials, however there is substantial baseline resistance and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include management of toxicities and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well tolerated and economical, they are likely to gain broader appeal. [ABSTRACT FROM AUTHOR]

Recently, microneedle systems have become an attractive solution for drug delivery. Traditionally, microneedle systems were fabricated via template molding methods. In this study, we present a novel method for the fabrication of a microneedle patch system. We used extrusion-based 3D printing and post stretching to fabricate a microneedle patch system for minimally invasive and glucose-responsive insulin delivery for diabetes treatment. First, we investigated the printability of various bioinks composed of alginate with hydroxyapatite as an additive. After printing the substrate and a cylindrical array of the patch, we stretched the top surface of the cylindrical array to form needle-like tips. The prepared microneedle patch contained 6 × 6 microneedles, and only the microneedles performed glucose-responsive release of insulin. Each microneedle was conical in shape, with a base diameter of 601 μm, a tip diameter of 24 μm, and a height of 643 μm. The fabricated microneedles exhibited sufficient mechanical strength to penetrate the skin of mice and responsively released insulin according to the glucose levels both in glucose solution and in type 1 diabetic mice. When transdermal application was performed only once on the skin of mice, the microneedle patches regulated the blood glucose levels of diabetic mice in normoglycemic ranges for up to 40 h and alleviated the diabetic symptoms of the mice. Our study proposed a method for the fabrication of microneedle patch systems, which can be potentially applied for transdermal drug delivery. • Extrusion-based 3D printing and post stretching are developed to prepare microneedle patch. • The formulations of bioinks are optimized to achieve 3D printing of the structures. • The microneedles show sufficient mechanical strength to penetrate the skin of mice. • The microneedles achieve transdermal drug delivery and glucose control in diabetic mice. [ABSTRACT FROM AUTHOR]

Chronic nonhealing wounds are a growing socioeconomic problem that affects more than 6 million people annually solely in the United States. These wounds are colonized by bacteria that often develop into biofilms that act as a physical and chemical barrier to therapeutics and tissue oxygenation leading to chronic inflammation and tissue hypoxia. Although wound debridement and vigorous mechanical abrasion techniques are often used by clinical professionals to manage and remove biofilms from wound surfaces, such methods are highly nonselective and painful. In this study, we have developed a flexible polymer composite microneedle array that can overcome the physicochemical barriers (i.e., bacterial biofilm) present in chronic nonhealing wounds and codeliver oxygen and bactericidal agents. The polymeric microneedles are made by using a facile UV polymerization process of polyvinylpyrrolidone and calcium peroxide onto a flexible polyethylene terephthalate substrate for conformable attachment onto different locations of the human body surface. The microneedles effectively elevate the oxygen levels from 8 to 12 ppm once dissolved over the course of 2 h while also providing strong bactericidal effects on both liquid and biofilm bacteria cultures of both Gram-positive ( Staphylococcus aureus ) and Gram-negative ( Pseudomonas aeruginosa ) bacterial strains commonly found in dermal wounds. Furthermore, the results from the ex vivo assay on a porcine wound model indicated successful insertion of the microneedles into the tissue while also providing effective bactericidal properties against both Gram-positive and Gram-negative within the complex tissue matrix. Additionally, the microneedles demonstrate high levels of cytocompatibility with less than 10% of apoptosis throughout 6 days of continuous exposure to human dermal fibroblast cells. The demonstrated flexible microneedle array can provide a better approach for increasing the effectiveness of topical tissue oxygenation as well as the treatment of infected wounds with intrinsically antibiotic resistant biofilms.

The extraction of interstitial fluid (ISF) from skin using microneedles (MNs) has attracted growing interest in recent years due to its potential for minimally invasive diagnostics and biosensors. ISF collection by absorption into a hydrogel MN patch is a promising way that requires the materials to have outstanding swelling ability. Here, a gelatin methacryloyl (GelMA) patch is developed with an 11 × 11 array of MNs for minimally invasive sampling of ISF. The properties of the patch can be tuned by altering the concentration of the GelMA prepolymer and the crosslinking time; patches are created with swelling ratios between 293% and 423% and compressive moduli between 3.34 MPa and 7.23 MPa. The optimized GelMA MN patch demonstrates efficient extraction of ISF. Furthermore, it efficiently and quantitatively detects glucose and vancomycin in ISF in an in vivo study. This minimally invasive approach of extracting ISF with a GelMA MN patch has the potential to complement blood sampling for the monitoring of target molecules from patients., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Interstitial fluid (ISF) that surrounds cells in tissues of the body is a novel source of biomarker that complements conventional sources like blood, urine, and saliva. To overcome difficulties in harvesting ISF, a minimally invasive, rapid, simple-to-use, cost-effective method is developed to collect ISF from the skin involving a microneedle (MN) patch. By pressing 650 µm long MNs at an angle just below the skin surface, blood-free ISF flows through micropores to the skin surface and is absorbed into a thin strip of paper on the MN patch backing for subsequent analysis. An optimized method in rat skin in vivo is well tolerated and able to collect >2 µL of ISF within 1 min. Brief skin pretreatment with MNs followed by a 5 min delay dramatically increases subsequent ISF collection by a mechanism believed to involve increased skin hydration. ISF collection using an MN patch has the potential to simplify access to biomarkers in ISF for research and future medical diagnostic and monitoring applications., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)