Hybrid Microneedle-Mediated Transdermal Delivery of Atorvastatin Calcium-Loaded Polymeric Micelles for Hyperlipidemia Therapy.

Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.

Assessing the structural stability and drug encapsulation efficiency of poly(ethylene glycol)-poly(L-lactic acid) nanoparticles loaded with atorvastatin calcium: Based on dissipative particle dynamics.

Block polymer micelles have been proven highly biocompatible and effective in improving drug utilization for delivering atorvastatin calcium. Therefore, it is of great significance to measure the stability of drug-loading nano micelles from the perspective of block polymer molecular sequence design, which would provide theoretical guidance for subsequent clinical applications. This study aims to investigate the structural stability of drug-loading micelles formed by two diblock/triblock polymers with various block sequences through coarse-grained dissipative particle dynamics (DPD) simulations. From the perspectives of the binding strength of poly(L-lactic acid) (PLLA) and polyethylene glycol (PEG) in nanoparticles, hydrophilic bead surface coverage, and the morphological alteration of nanoparticles induced by shear force, the ratio of hydrophilic/hydrophobic sequence length has been observed to affect the stability of nanoparticles. We have found that for diblock polymers, PEG3kda-PLLA2kda has the best stability (corresponding hydrophilic coverage ratio is 0.832), while PEG4kda-PLLA5kda has the worst (coverage ratio 0.578). For triblock polymers, PEG4kda-PLLA2kda-PEG4kda has the best stability (0.838), while PEG4kda-PLLA5kda-PEG4kda possesses the worst performance (0.731), and the average performance on stability is better than nanoparticles composed of diblock polymers.

Aggregation-induced emission photosensitizer microneedles for enhanced melanoma photodynamic therapy.

The incidence and mortality rates of skin melanoma have been increasing annually. Photodynamic therapy (PDT) enables effective destruction of tumor cells while minimizing harm to normal cells. However, traditional photosensitizers (PSs) suffer from photobleaching, photodegradation and the aggregation-caused quenching (ACQ) effect, and it is challenging for light to reach the deep layers of the skin to maximize the efficacy of PSs. Herein, we developed dissolving microneedles (MNs) loaded with PSs of TPE-EPy@CB[7] through supramolecular assembly. The PSs effectively enhanced the type-I reactive oxygen species (ROS) generation capacity, with a concentration of 2 µM possessing nearly half of the tumor cell-killing ability under 10 min white light irradiation. The MNs were successfully pierced into the targeted site for precise drug delivery. Additionally, the conical structure of the MNs, as well as the lens-like structure after dissolution, facilitated the transmission of light in the subcutaneous tissue, achieving significant inhibition of tumor growth with a tumor suppression rate of 97.8% and no systemic toxicity or side effects in melanoma mice. The results demonstrated the potent melanoma inhibition and biosafety of this treatment approach, exhibiting a new and promising strategy to conquer malignant melanoma.

Toward a solid microneedle patch for rapid and enhanced local analgesic action.

Analgesic creams find widespread application as adjuncts for localized anesthesia prior to surgical procedures. Nevertheless, the onset of analgesic action is protracted due to the skin barrier's inherent characteristics, which necessitates prolonged intervals of patient and clinician waiting, consequently impinging upon patient compliance and clinician workflow efficiency. In this work, a biodegradable microneedles (MNs) patch was introduced to enhance the intradermal administration of lidocaine cream to achieve rapid analgesia through a minimally invasive and conveniently accessible modality. The polylactic acid (PLA) MNs were mass-produced using a simple hot-pressing method and served the purpose of creating microchannels across the skin's surface for rapid absorption of lidocaine cream. Optical and electron microscopes were applied to meticulously scrutinize the morphology of the fabricated MNs, and the comprehensive penetration tests involving dynamometer tests, evaluation on porcine cadaver skin, artificial film, optical coherence tomography (OCT), transepidermal water loss, and analysis on rats' skins, demonstrated the robust mechanical strength of PLA MNs for successful intradermal penetration. The behavioral pain sensitivity tests on living rats using Von Frey hair filaments revealed that the MN-assisted lidocaine treatment expeditiously accelerated the onset of action from 40 to 10 min and substantially enhanced the efficacy of localized anesthesia. Furthermore, different treatment protocols encompassing the sequence of drug application relative to MN treatment, MN dimensions, and the frequency of MN insertions exhibited noteworthy influence on the resultant local anesthesia efficacy. Together, these results demonstrated that the lidocaine cream followed by diverse PLA MN treatments would be a promising strategy for rapid clinical local anesthesia with wide-ranging applications.

Functional insulin aspart/insulin degludec-based microneedles for promoting postprandial glycemic control.

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.

Multifunctional Covalent Organic Framework-Based Microneedle Patch for Melanoma Treatment.

Melanoma is resistant to conventional chemotherapy and radiotherapy. Therefore, it is essential to develop a targeted, low-toxic, and minimally invasive treatment. Here, DTIC/ICG-Fe3O4@TpBD BSP/HA microneedles (MNs) were designed and fabricated, which can enhance targeting to melanoma and perform photothermal therapy (PTT) and chemotherapy simultaneously to synergistically exert anticancer effects. The system consisted of magnetic nanoparticles (DTIC/ICG-Fe3O4@TpBD), dissoluble matrix (Bletilla polysaccharide (BSP)/hyaluronic acid (HA)), and a polyvinyl alcohol backing layer. Due to the good magnetic responsiveness of Fe3O4@TpBD, dacarbazine (DTIC) and indocyanine green (ICG) can be better targeted to the tumor tissue and improve the therapeutic effect. BSP and HA have good biocompatibility and transdermal ability, so that the MNs can completely penetrate the tumor tissue, be dissolved by the interstitial fluid, and release DTIC and ICG. Under near-infrared (NIR) light irradiation, ICG converts light energy into thermal energy and induces ablation of B16-OVA melanoma cells. In vivo results showed that DTIC/ICG-Fe3O4@TpBD BSP/HA MNs combined with chemotherapy and PTT could effectively inhibit the growth of melanoma without tumor recurrence or significant weight loss in mice. Therefore, DTIC/ICG-Fe3O4@TpBD BSP/HA MNs are expected to provide new ideas and therapeutic approaches for the clinical treatment of melanoma.

Microneedles: a novel strategy for wound management.

Wound management is a serious concern worldwide, inflicting a huge social and economic burden on patients and healthcare systems, and research into efficient wound-management measures is crucial. Although advances have been made in traditional wound dressings for wound management to date, the complicated environment near the wound leads to inadequate drug absorption for achieving the intended therapeutic impact. Microneedles, a novel transdermal drug delivery method, can improve wound-healing efficacy by breaking down the barriers at the wound site and enhancing drug delivery efficiency. In recent years, there have been many advanced types of research on the application of microneedles to wound management to address the difficulties encountered in the wound-healing process. This article summarizes and analyzes these research efforts, classifying them according to their distinct efficacy, and addresses them in five areas: hemostasis, antibacterial effects, proliferation, anti-scar, and wound monitoring. The article concludes with a review of the current state and limitations of microneedle patches and an outlook on the future direction of microneedles in wound management as a way to inspire more efficient and smarter wound-management strategies.

A photoactive injectable antibacterial hydrogel to support chemo-immunotherapeutic effect of antigenic cell membrane and sorafenib by near-infrared light mediated tumor ablation.

Intravenously administered nanocarriers suffer from off-target distribution, pre-targeting drug leakage, and rapid clearance, limiting their efficiency in tumor eradication. To bypass these challenges, an injectable hydrogel with time- and temperature-dependent viscosity enhancement behavior and self-healing property are reported to assist in the retention of the hydrogel in the tumor site after injection. The cancer cell membrane (CCM) and sorafenib are embedded into the hydrogel to elicit local tumor-specific immune responses and induce cancer cell apoptosis, respectively. In addition, hyaluronic acid (HA) coated Bi2S3 nanorods (BiH) are incorporated within the hydrogel to afford prolonged multi-cycle local photothermal therapy (PTT) due to the reduced diffusion of the nanorods to the surrounding tissues as a result of HA affinity toward cancer cells. The results show the promotion of immunostimulatory responses by both CCM and PTT through the release of inflammatory cytokines from immune cells, which allows localized and complete ablation of the breast tumor in an animal model by a single injection of the hydrogel. Moreover, the BiH renders strong antibacterial activity to the hydrogel, which is crucial for the clinical translation of injectable hydrogels as it minimizes the risk of infection in the post-cancer lesion formed by PTT-mediated cancer therapy.

Hydroquinone cream-based polymer microneedle roller for the combined treatment of large-area chloasma.

Melasma is a common hyperpigmented skin condition that occurs on the face and other areas prone to light exposure, seriously affecting people's quality of life. Microneedle, a new type of transdermal drug delivery device, can significantly improve skin permeability. In this study, we designed and fabricated a polymer microneedle roller (PMR) using a mold hot pressing method, and established a mouse model of melasma induced by ultraviolet radiation. The dynamometer and insertion test of MNs into parafilm and skin of mice indicates that the MNs have sufficient mechanical properties to insert parafilm and skin of mice. The two methods (apply hydroquinone cream (HQC) directly and pre-treat with PMR before applying HQC) were used to treat melasma. From the results of skin surface observation, determination of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in skin and liver tissues, histological observation, and skin Optical coherence tomography (OCT), we confirmed both the two methods had a therapeutic effect while the PMR pretreatment group exhibited a better therapeutic effect. In addition, there were statistical differences between the UV group (P < 0.05). Together these results indicated that the MNs may be promising in future clinical applications in improving the UV irradiation-induced pigmentation like melisma.

Living Leukocyte-Based Drug Delivery Systems.

Leukocytes play a vital role in immune responses, including defending against invasive pathogens, reconstructing impaired tissue, and maintaining immune homeostasis. When the immune system is activated in vivo, leukocytes accomplish a series of orderly and complex regulatory processes. While cancer and inflammation-related diseases like sepsis are critical medical difficulties plaguing humankind around the world, leukocytes have been shown to largely gather at the focal site, and significantly contribute to inflammation and cancer progression. Therefore, the living leukocyte-based drug delivery systems have attracted considerable attention in recent years due to the innate and specific targeting effect, low immunogenicity, improved therapeutic efficacy, and low reverse effect. In this review, the recent advances in the development of living leukocyte-based drug delivery systems including macrophages, neutrophils, and lymphocytes as promising treatment strategies for cancer and inflammation-related diseases are introduced. The advantages, current challenges, and limitations of these delivery systems are also discussed, as well as perspectives on the future development of precision and targeted therapy in the clinics are provided. Collectively, it is expected that such kind of living cell-based drug delivery system is promising to improve or even revolutionize the treatments of cancers and inflammation-related diseases in the clinics.

Subcutaneous Implantable Microneedle System for the Treatment of Alzheimer's Disease by Delivering Donepezil.

To alleviate the dilemma of drug administration in Alzheimer's disease (AD) patients, it is of great significance to develop a new drug delivery system. In this study, a subcutaneously implanted microneedle (MN) device with a swellable gelatin methacryloyl (GelMA) needle body and a dissolvable polyvinyl alcohol (PVA) backing layer was designed. The backing layer quickly dissolved once the MN was introduced into the subcutaneous, and the hydrogel needles were implanted in the subcutaneous to enable prolonged drug release. Compared with oral administration, the MN system offers the benefits of a high administration rate, a fast onset of effect, and a longer duration of action. By detecting the concentration of acetylcholine (ACH) and Aß 1-42, it was found that MN administration exhibited a stronger therapeutic effect. The biological safety of the MN system was also assessed, and no obvious signs of hemolysis, cytotoxicity, and inflammatory reaction were observed. Together, these findings suggested that the MN system is a convenient, efficient, and safe method of delivering donepezil hydrochloride (DPH) and may provide AD patients with a novel medicine administration option.

Improved pharmacodynamics of epidermal growth factor via microneedles-based self-powered transcutaneous electrical stimulation.

Epidermal growth factor is an excellent drug for promoting wound healing; however, its conventional administration strategies are associated with pharmacodynamic challenges, such as low transdermal permeability, reduction, and receptor desensitization. Here, we develop a microneedle-based self-powered transcutaneous electrical stimulation system (mn-STESS) by integrating a sliding free-standing triboelectric nanogenerator with a microneedle patch to achieve improved epidermal growth factor pharmacodynamics. We show that the mn-STESS facilitates drug penetration and utilization by using microneedles to pierce the stratum corneum. More importantly, we find that it converts the mechanical energy of finger sliding into electricity and mediates transcutaneous electrical stimulation through microneedles. We demonstrate that the electrical stimulation applied by mn-STESS acts as an "adjuvant" that suppresses the reduction of epidermal growth factor by glutathione and upregulates its receptor expression in keratinocyte cells, successfully compensating for receptor desensitization. Collectively, this work highlights the promise of self-powered electrical adjuvants in improving drug pharmacodynamics, creating combinatorial therapeutic strategies for traditional drugs.

Evaluation of Nanoparticle Stability under Blood Flow Shear.

The stability of drug-loaded nanoparticles in vivo is related to the success of the drug delivery, which is investigated as a deficiency due to the limitation of traditional experimental methods. In this study, dissipative particle dynamics (DPD), a simulation method suitable for soft matter and fluids, was used to study the stability of amphiphilic nanoparticles in the blood microenvironment. By comparing the morphology alteration of nanoparticles with various molecular topologies in the shear fluid field, we have found that branch degree and geometric symmetry would be the key factors in maintaining the nanoparticle's stability. This research could provide more theoretical guidance for drug delivery system design.

Thermosensitive hydrogel microneedles for controlled transdermal drug delivery.

By using the prominent merit of poly(N-isopropylacrylamide) (PNIPAm) that can reversibly switch from a linear state to a coiled state with the change in temperature, in this work, gelatin was grafted with carboxylic end-capped PNIPAm as the matrix material to fabricate a physical entanglement crosslinked hydrogel microneedles (MNs) patch that can control drug release after application on the skin. The crystallization of the drug during the fabrication process of MNs was decreased due to the thermo-reversible sol-gel transition of the matrix materials. In addition, to increase the mechanical strength of the MNs and to decrease the application time, the gelatin-g-PNIPAm (GP) MNs patch was mounted onto solid MNs to fabricate a rapidly separating MNs system (RS-GP-MNs). The combination of the rapidly separating technique and the thermosensitive hydrogel provides the combined ability to efficiently deliver drug-loaded MNs into the skin within few seconds and to control drug release within the skin. Through a series of tests, we found that RS-GP-MNs showed suitable lower critical solution temperature and adequate crosslinking speed for practical application. The hypoglycemic effect in diabetic mice was characteristically controlled by insulin release through RS-GP-MNs as compared to the MNs made from unmodified gelatin. The proposed RS-GP-MNs system is potentially applicable to various hydrophilic small molecular and peptide medicines that require frequent dosing, thus providing an effective, noninvasive, and painless administration method with minimal safety concerns. STATEMENT OF SIGNIFICANCE: 1. Hydrogel microneedles that can be reversibly triggered and controllably release drugs at body temperature were fabricated. 2. Hydrogel microneedles prepared from gelatin-g-PNIPAm can avoid the use of a molecular crosslinker that is toxic and difficult to be completely removed. 3. Gelatin-g-PNIPAm with thermosensitive property showed appropriate molecular interactions with the drug and slowed down the crystallization speed of the drug in the solution.

An update on biomaterials as microneedle matrixes for biomedical applications.

Microneedles (MNs) have been developed for various applications such as drug delivery, cosmetics, diagnosis, and biosensing. To meet the requirements of MNs used in these areas, numerous materials have been used for the fabrication of MNs. However, MNs will be exposed to skin tissues after piercing the stratum corneum barrier. Thus, it is necessary to ensure that the matrix materials of MNs have the characteristics of low toxicity, good biocompatibility, biodegradability, and sufficient mechanical properties for clinical application. In this review, the matrix materials currently used for preparing MNs are summarized and reviewed in terms of these factors. In addition, MN products used on the market and their applications are summarized in the end. This work may provide some basic information to researchers in the selection of MN matrix materials and in developing new materials.

Conductive Microneedle Patch with Electricity-Triggered Drug Release Performance for Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that seriously affects the life quality of patients. Topical administration of glucocorticoids is considered to be the most effective anti-inflammatory treatment. However, due to the barrier function of skin, only less than 20% of topical drug molecules could diffuse into the skin. Therefore, it is of great importance to develop an effective strategy to improve AD therapy. In this study, we reported a two-electrode microneedle patch (t-EMNP) composed of a polylactic acid-platinum (PLA-Pt) MN array and polylactic acid-platinum-polypyrrole (PLA-Pt-PPy) MN array for improving the transdermal drug delivery efficacy. The drug loading capability of MNs could be altered by employing different polymerization times and drug concentrations. The drug release rate of MNs could be changed by applying different voltages. We further developed a controlled transdermal drug delivery system (c-TDDS) based on this two-electrode microneedle patch (t-EMNP), exhibiting the remarkable performance of the electricity-triggered drug release profile. The drugs could be released with electrical stimulation, while there was almost no drug release without electrical stimulation. For AD treatment in vivo, this MN patch with electricity-triggered drug release performance could effectively deliver more drugs into the skin compared with other controls such as dexamethasone cream, which efficiently alleviate AD. In sum, this work not only developed a smart patch for improving AD treatment but also provided a promising approach of transdermal drug delivery on demand.

Microneedle-based technology for cell therapy: current status and future directions.

With the growing technological innovations in medical treatments, cell-based therapies hold great potential as efficient tools against various previously incurable diseases by restoring or altering the function of certain sets of cells. Along this line, an essential factor to determine the success of cell therapy is the choice of cell delivery strategy. In recent years, a novel trend is blooming in the application of microneedle systems, which are based on the miniaturization of multiple needles within a patch to the micrometer dimensions, aimed at the delivery of therapeutic cells to the target site with high efficiency and in a minimally invasive manner. This review aims to demonstrate the advantages of exploiting microneedle-based technology as a new tool for cell therapy. The advancements of microneedle-based strategies for cell delivery are summarized in terms of two categories: cell-free and cell-loaded microneedle systems. The majority of research on microneedle-based cell therapy has shown promising results for tissue regeneration, cancer immunotherapy, skin immune monitoring and targeted cell delivery. Finally, current challenges and future perspectives toward the development and application of microneedles for cell therapy are also discussed.

A high-dosage microneedle for programmable lidocaine delivery and enhanced local long-lasting analgesia.

Considering the staggering global prevalence of local pain affecting hundreds of million individuals, it is of great significance to develop advanced dosage forms or delivery systems for analgesic therapy to fulfill clinical applicability. In this study, a hydrogel microneedles (MNs) system made out of gelatin-methacryloyl (GelMA) was designed to deliver lidocaine hydrochloride (LiH) in a sustained manner, and the drug loading capacity of the GelMA MNs was increased considerably by using the backing layer reservoir. The in vitro and in vivo tests showed that the fabricated GelMA MNs are strong enough for reliable skin application, and achieve high drug delivery efficiency as compared with the commercial lidocaine patches. The Spared-nerve injury (SNI) model of rats was also prepared to test behavioral pain sensitivity in response to mechanical stimuli, which proved that the LiH/GelMA MNs can enhance and prolong the anesthetic effect of LiH. In addition, with biosafety evaluation in rats, the MNs treated site restored to normal appearance within several hours of application and no dermatosis-related side effects or behavior disorders were observed during the experiment. Together these results indicated that the use of GelMA MNs for transdermal delivery of LiH is an effective, safe and simple treatment method to provide a better choice for local long-lasting analgesia.

A novel method for fabrication of coated microneedles with homogeneous and controllable drug dosage for transdermal drug delivery.

Over the years, scientists have been focused on the development of microneedle coating process to coat a broad range of therapeutic agents onto the surface of the solid microneedles for effective drug delivery. The precise dose control, content uniformity as well as large-scale production of coated microneedles are still the core issues that have been the interest of researchers in this topic. To this end, a repeatable method that involved a micro-molding process was demonstrated for mass fabrication of coated microneedles with homogeneous and controllable drug loading under mild conditions. In this system, the dissolvable drug carriers with precise dosage were first mounted onto the solid microneedles and then exposed to the high moisture condition to finally obtain the coated microneedle with uniform and precise drug loading. Using the microneedle molds with the volume of 4.71 nL, 8.24 nL, 10.47 nL, and 12.56 nL per cavity, the drug loadings were precisely controlled at 4.8 ng, 6.4 ng, 9.3 ng, and 13.5 ng per needle, with the standard deviation of 0.09, 0.01, 0.07, and 0.53%, respectively. Mechanical property tests showed that the coated microneedles are strong enough for reliable skin insertion, and with in vivo trials in diabetic mice, we further confirmed the similar hypoglycaemic effect of insulin-coated microneedles to subcutaneous injection. Taken together, the micro-molding-based fabrication process has practical merits in the mass production of coated microneedles with homogeneous and controllable drug loading, facilitating the clinical translation of the microneedle technique.

An update on microneedle-based systems for diabetes.

Diabetes is one of the most serious chronic diseases today. Patients with diabetes need frequent insulin injections or blood sampling to monitor blood glucose levels. The microneedles are a painless transdermal drug delivery system, which has great advantages in achieving self-management. There have been a lot of researches on microneedles used in diabetes treatment. Microneedle-based treatment of diabetes has also changed from a simple and reliable system to a complex and efficient system. This review introduces microfluidic, glucose response, and other contents based on microneedles, and some challenges in the development of microneedles.