On-demand drug delivery bioelectronics through a water-processable low dimensional highly conductive MXene layer.

On-demand drug delivery holds great promise to optimize pharmaceutical efficacy while minimizing the side effects. However, existing on-demand drug delivery systems often require complicated manufacturing processes that preclude their wide implementation of a broad range of drugs. In this work, we demonstrate the introduction of MXene-coated microneedles (MNs) into bioelectronics for digitally controllable gate-valve drug delivery. MXenes, featuring high electronic conductivity, excellent biocompatibility, and solution processibility, enable low-cost scalability for printable bioelectronics. In an electrolytic state (e.g., body fluid), the coated MXene is oxidized and desorbed due to redox reactions caused by electrical bias, allowing the underlying drug to be controllably released. The MXene-incorporated drug delivery system not only demonstrates excellent biocompatibility and operational stability, but also features low-cost construction and sustainable usage. Besides, these MXene-coated MNs allow both on-demand transformation and local-region customization, further increasing the structural versatility and capability of multidrug delivery systems.

Poly­d,l­lactic acid­enhanced atrophic scar treatment via transdermal microjet drug delivery in Asians.

BACKGROUND: Acne vulgaris often results in permanent scars, with atrophic scars being the most common type and posing a significant therapeutic challenge due to their prevalence and impact on patients' quality of life. Various treatment options exist, including the use of poly-d,l-lactic acid delivered via different methods. OBJECTIVE: This study aimed to assess the efficacy and safety of poly-d,l-lactic acid delivered via laser-assisted needle-free microjet injection for treating atrophic scars. METHODS: Five Korean participants with atrophic facial scars were recruited. Poly-d,l-lactic acid solution was administered via the Mirajet system in five sessions, with clinical assessments conducted at baseline, before each session, and at 12-week and 22-week follow-ups. Outcome measures included the Global Aesthetic Improvement Scale and patient satisfaction scores. RESULTS: Positive results were observed at the 12-week and 22-week follow-ups, with high patient satisfaction and improvements in atrophic scars and skin texture. Mild discomfort and transient side effects were reported, with no adverse events observed during the follow-up period. CONCLUSION: Poly-d,l-lactic acid delivered by a laser-assisted needle-free microjet injector was judged to be effective for improving atrophic the facial area. Further research, particularly through randomized controlled trials, is needed to validate these findings and assess the longer-term safety and sustainability of outcomes.

Self-Assembled Multilayer-Modified Needles Simulate Acupuncture and Diclofenac Sodium Delivery for Rheumatoid Arthritis.

A novel therapeutic approach combining acupuncture and diclofenac sodium (DS) administration was established for the potential treatment for rheumatoid arthritis (RA). DS is a commonly used anti-inflammatory and analgesic drug but has short duration and adverse effects. Acupoints are critical linkages in the meridian system and are potential candidates for drug delivery. Herein, we fabricated a DS-loaded multilayer-modified acupuncture needle (DS-MMAN) and investigated its capacity for inhibiting RA. This DS-MMAN possesses sustained release properties and in vitro anti-inflammatory effects. Experimental results showed that the DS-MMAN with microdoses can enhance analgesia and efficiently relieve joint swelling compared to the oral or intra-articular administration of DS with gram-level doses. Moreover, the combination of acupoint and DS exerts a synergistic improvement in inflammation and joint damage. Cytokine and T cell analyses in the serum indicated that the application of DS-MMAN suppressed the levels of pro-inflammatory factors and increased the levels of anti-inflammatory factors. Furthermore, the acupoint administration via DS-MMAN could decrease the accumulation of DS in the liver and kidneys, which may express better therapeutic efficiency and low toxicity. The present study demonstrated that the acupuncture needle has the potential to build a bridge between acupuncture and medication, which would be a promising alternative to the combination of traditional and modern medicine.

Semi-invasive wearable clinic: Solution-processed smart microneedle electronics for next-generation integrated diagnosis and treatment.

The integrated smart electronics for real-time monitoring and personalized therapy of disease-related analytes have been gradually gaining tremendous attention. However, human tissue barriers, including the skin barrier and brain-blood barrier, pose significant challenges for effective biomarker detection and drug delivery. Microneedle (MN) electronics present a promising solution to overcome these tissue barriers due to their semi-invasive structures, enabling effective drug delivery and target-analyte detection without compromising the tissue configuration. Furthermore, MNs can be fabricated through solution processing, facilitating large-scale manufacturing. This review provides a comprehensive summary of the recent three-year advancements in smart MNs development, categorized as follows. First, the solution-processed technology for MNs is introduced, with a focus on various printing technologies. Subsequently, smart MNs designed for sensing, drug delivery, and integrated systems combining diagnosis and treatment are separately summarized. Finally, the prospective and promising applications of next-generation MNs within mediated diagnosis and treatment systems are discussed.

Advances in the Design of Functional Cellulose Based Nanopesticide Delivery Systems.

The advancement of science and technology, coupled with the growing environmental consciousness among individuals, has led to a shift in pesticide development from traditional methods characterized by inefficiency and misuse toward a more sustainable and eco-friendly approach. Cellulose, as the most abundant natural renewable resource, has opened up a new avenue in the field of biobased drug carriers by developing cellulose-based drug delivery systems. These systems offer unique advantages in terms of deposition rate enhancement, modification facilitation, and environmental impact reduction when designing nanopesticides. Consequently, their application in the field of nanoscale pesticides has gained widespread recognition. The present study provides a comprehensive review of cellulose modification methods, carrier types for cellulose-based nanopesticides delivery systems (CPDS), and various stimulus-response factors influencing pesticide release. Additionally, the main challenges in the design and application of CPDS are summarized, highlighting the immense potential of cellulose-based materials in the field of nanopesticides.

Pre-ANDA strategy and Human Factors activities to de-risk pharmaceutical companies ANDA submission of drug-device combination products: case study of a formative Comparative Use Human Factors study.

BACKGROUND: This article presents a strategy that a Drug Delivery Device Developer (DDDD) has adopted to support Abbreviated New Drug Application (ANDA) submissions of drug-device combination products. As per the related FDA guidance, a threshold analysis should be compiled. If 'other differences' between the Reference Listed Drug (RLD) and the generic drug devices are identified, a Comparative Use Human Factors (CUHF) study may be requested. METHODS: The DDDD performed task analysis and physical comparison to assess the pen injector design differences. Then, a formative CUHF study with 25 participants simulating injections using both RLD and the generic pen injectors was conducted. RESULTS: After each participant completed four simulated injections, similar type and rates of use error between the RLD (0.70) and generic (0.68) pen injectors were observed. CONCLUSION: DDDDs can support pharmaceutical companies in the ANDA submission strategy of their drug-device combination product by initiating comparative task analysis and physical comparison of the device as inputs for the threshold analysis. If 'other differences' are identified, a formative CUHF study can be performed. As shown in our case study, this approach can be leveraged to support the sample size calculation and non-inferiority margin determination for a CUHF study with the final combination product.

Optimizing anthocyanin Oral delivery: Effects of food biomacromolecule types on Nanocarrier performance for enhanced bioavailability.

Wall material types influence the efficacy of nanocarriers in oral delivery systems. We utilized three food biomacromolecules (whey protein isolate, oxidized starch, lipids) to prepare three types of nanocarriers. Our aim was to investigate their performance in digestion, cellular absorption, mucus penetration, intestinal retention, and bioavailability of the encapsulated anthocyanins (Ant). The release rate of protein nanocarriers (Pro-NCs) was twice that of starch nanocarriers (Sta-NCs) and four times that of lipid nanocarriers (Lip-NCs) in simulated gastrointestinal fluid. Additionally, Pro-NCs demonstrated superior transmembrane transport capacity and over three times cellular internalization efficiency than Sta-NCs and Lip-NCs. Sta-NCs exhibited the highest mucus-penetrating capacity, while Pro-NCs displayed the strongest mucoadhesion, resulting in extended gastrointestinal retention time for Pro-NCs. Sta-NCs significantly enhanced the in vivo bioavailability of Ant, nearly twice that of free Ant. Our results demonstrate the critical role of wall material types in optimizing nanocarriers for the specific delivery of bioactive compounds.

Numerical modeling of ultrasound-triggered microneedle-mediated delivery of drug particles into bacterial biofilms.

Ultrasonic microneedle patches, a class of ultrasound-driven transdermal drug delivery systems, are promising in addressing bacterial biofilms. This device has been proven to be more effective in treating Staphylococcus aureus biofilms than drug in free solution. However, there exists a notable gap in understanding how various excitation conditions and material parameters affect drug delivery efficiency. This study aims to fill this void by conducting an comprehensive multi-physics numerical analysis of ultrasonic microneedle patches, with the ultimate goal of enhancing drug delivery. First, we investigate the impact of various ultrasound frequencies on drug penetration depths. The findings reveal that local resonance can accelerate drug release within a shorter time window (first 1.5 h), whereas non-resonant frequencies enable more profound and prolonged diffusion. This information is crucial for medical professionals in selecting the most effective frequency for optimal drug administration. Furthermore, our investigation extends to the effects of applied voltage on temperature distribution, a critical aspect for ensuring medical safety during the application of these patches. Additionally, we examine how particles of different sizes respond to acoustic pressure and streaming fields, providing valuable insights for tailoring drug delivery strategies to specific therapeutic needs. Overall, our findings offer comprehensive guidelines for the effective use of ultrasonic microneedle patches, potentially shifting the paradigm in patient care and enhancing the overall quality of life.

Multifunctional nanomaterials for smart wearable diabetic healthcare devices.

Wearable diabetic healthcare devices have attracted great attention for real-time continuous glucose monitoring (CGM) using biofluids such as tears, sweat, saliva, and interstitial fluid via noninvasive ways. In response to the escalating global demand for CGM, these devices enable proactive management and intervention of diabetic patients with incorporated drug delivery systems (DDSs). In this context, multifunctional nanomaterials can trigger the development of innovative sensing and management platforms to facilitate real-time selective glucose monitoring with remarkable sensitivity, on-demand drug delivery, and wireless power and data transmission. The seamless integration into wearable devices ensures patient's compliance. This comprehensive review evaluates the multifaceted roles of these materials in wearable diabetic healthcare devices, comparing their glucose sensing capabilities with conventionally available glucometers and CGM devices, and finally outlines the merits, limitations, and prospects of these devices. This review would serve as a valuable resource, elucidating the intricate functions of nanomaterials for the successful development of advanced wearable devices in diabetes management.

Effect of Microsphere Concentration on Catechin Release from Microneedle Arrays.

In this work, microspheres were developed by cross-linking glutaraldehyde in an aqueous gelatin solution with a surfactant and solvent. A poly(vinyl alcohol) (PVA) solution was produced and combined with catechin-loaded microspheres. Different microsphere concentrations (0%, 5%, 10%, and 15%) were applied to the PVA microneedles. The moisture content, particle size, swelling, and drug release percentage of microneedles were studied using various microsphere concentrations. Fourier transform infrared and scanning electron microscopy (SEM) investigations validated the structure of gelatin microspheres as well as their decoration in microneedles. The SEM scans revealed that spherical microspheres with a wrinkled and folded morphology were created, with no physical holes visible on the surface. The gelatin microspheres generated had a mean particle size of 20-30 µm. Ex vivo release analysis indicated that microneedles containing 10% microspheres released the most catechin, with 42.9% at 12 h and 84.4% at 24 h.

A reconfigurable integrated smart device for real-time monitoring and synergistic treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a global autoimmune disease that requires long-term management. Ambulatory monitoring and treatment of RA favors remission and rehabilitation. Here, we developed a wearable reconfigurable integrated smart device (ISD) for real-time inflammatory monitoring and synergistic therapy of RA. The device establishes an electrical-coupling and substance delivery interfaces with the skin through template-free conductive polymer microneedles that exhibit high capacitance, low impedance, and appropriate mechanical properties. The reconfigurable electronics drive the microneedle-skin interfaces to monitor tissue impedance and on-demand drug delivery. Studies in vitro demonstrated the anti-inflammatory effect of electrical stimulation on macrophages and revealed the molecular mechanism. In a rodent model, impedance sensing was validated to hint inflammation condition and facilitate diagnosis through machine learning model. The outcome of subsequent synergistic therapy showed notable relief of symptoms, elimination of synovial inflammation, and avoidance of bone destruction.

Delivering biochemicals with precision using bioelectronic devices enhanced with feedback control.

Precision medicine endeavors to personalize treatments, considering individual variations in patient responses based on factors like genetic mutations, age, and diet. Integrating this approach dynamically, bioelectronics equipped with real-time sensing and intelligent actuation present a promising avenue. Devices such as ion pumps hold potential for precise therapeutic drug delivery, a pivotal aspect of effective precision medicine. However, implementing bioelectronic devices in precision medicine encounters formidable challenges. Variability in device performance due to fabrication inconsistencies and operational limitations, including voltage saturation, presents significant hurdles. To address this, closed-loop control with adaptive capabilities and explicit handling of saturation becomes imperative. Our research introduces an enhanced sliding mode controller capable of managing saturation, adept at satisfactory control actions amidst model uncertainties. To evaluate the controller's effectiveness, we conducted in silico experiments using an extended mathematical model of the proton pump. Subsequently, we compared the performance of our developed controller with classical Proportional Integral Derivative (PID) and machine learning (ML)-based controllers. Furthermore, in vitro experiments assessed the controller's efficacy using various reference signals for controlled Fluoxetine delivery. These experiments showcased consistent performance across diverse input signals, maintaining the current value near the reference with a relative error of less than 7% in all trials. Our findings underscore the potential of the developed controller to address challenges in bioelectronic device implementation, offering reliable precision in drug delivery strategies within the realm of precision medicine.

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

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

The Effects of Inspiratory Flows, Inspiratory Pause, and Suction Catheter on Aerosol Drug Delivery with Vibrating Mesh Nebulizers During Mechanical Ventilation.

Background: Some experts recommend specific ventilator settings during nebulization for mechanically ventilated patients, such as inspiratory pause, high inspiratory to expiratory ratio, and so on. However, it is unclear whether those settings improve aerosol delivery. Thus, we aimed to evaluate the impact of ventilator settings on aerosol delivery during mechanical ventilation (MV). Methods: Salbutamol (5.0 mg/2.5 mL) was nebulized by a vibrating mesh nebulizer (VMN) in an adult MV model. VMN was placed at the inlet of humidifier and 15 cm away from the Y-piece of the inspiratory limb. Eight scenarios with different ventilator settings were compared with endotracheal tube (ETT) connecting 15 cm from the Y-piece, including tidal volumes of 6-8 mL/kg, respiratory rates of 12-20 breaths/min, inspiratory time of 1.0-2.5 seconds, inspiratory pause of 0-0.3 seconds, and bias flow of 3.5 L/min. In-line suction catheter was utilized in two scenarios. Delivered drug distal to the ETT was collected by a filter, and drug was assayed by an ultraviolet spectrophotometry (276 nm). Results: Compared to the use of inspiratory pause, the inhaled dose without inspiratory pause was either higher or similar across all ventilation settings. Inhaled dose was negatively correlated with inspiratory flow with VMN placed at 15 cm away from the Y-piece (rs = -0.68, p < 0.001) and at the inlet of humidifier (rs = -0.83, p < 0.001). The utilization of in-line suction catheter reduced inhaled dose, regardless of the ventilator settings and nebulizer placements. Conclusions: When VMN was placed at the inlet of humidifier, directly connecting the Y-piece to ETT without a suction catheter improved aerosol delivery. In this configuration, the inhaled dose increased as the inspiratory flow decreased, inspiratory pause had either no or a negative impact on aerosol delivery. The inhaled dose was greater with VMN placed at the inlet of humidifier than 15 cm away the Y-piece.

A Glucose-Responsive Cannula for Automated and Electronics-Free Insulin Delivery.

Automated delivery of insulin based on continuous glucose monitoring is revolutionizing the way insulin-dependent diabetes is treated. However, challenges remain for the widespread adoption of these systems, including the requirement of a separate glucose sensor, sophisticated electronics and algorithms, and the need for significant user input to operate these costly therapies. Herein, a user-centric glucose-responsive cannula is reported for electronics-free insulin delivery. The cannula-made from a tough, elastomer-hydrogel hybrid membrane formed through a one-pot solvent exchange method-changes permeability to release insulin rapidly upon physiologically relevant varying glucose levels, providing simple and automated insulin delivery with no additional hardware or software. Two prototypes of the cannula are evaluated in insulin-deficient diabetic mice. The first cannula-an ends-sealed, subcutaneously inserted prototype-normalizes blood glucose levels for 3 d and controls postprandial glucose levels. The second, more translational version-a cannula with the distal end sealed and the proximal end connected to a transcutaneous injection port-likewise demonstrates tight, 3-d regulation of blood glucose levels when refilled twice daily. This proof-of-concept study may aid in the development of "smart" cannulas and next-generation insulin therapies at a reduced burden-of-care toll and cost to end-users.

Percutaneous delivery of liquid tetracycline using a thermal resurfacing drug delivery system for the treatment of festoons.

OBJECTIVES: To examine the effects of percutaneous tetracycline delivery to the malar area using a thermomechanical device (Tixel) in patients suffering from festoons. METHODS: This retrospective study included patients who underwent combination treatment with a thermomechanical device (Tixel) followed by application of topical tetracycline 1% at two private clinics between 2019 and 2023. Demographic and medical data, treatment parameters along with before and after treatment photographs were retrieved retrospectively. All patients were asked to answer a questionnaire, assessing self-reported pre and posttreatment disturbance, patient global impression of change (PGIC) score, overall satisfaction with treatment, and the onset and duration of treatment effect. Finally, three masked reviewers evaluated and graded the severity of before and after treatment photographs. RESULTS: Twenty healthy patients received the combination treatment. The mean age was 59.4 ± 8.2 years (range: 45-72 years), and 90.0% (n = 18) were female. The number of treatment sessions per patient ranged from 2 to 8, mean of 5.0 ± 1.9, performed at 5.4 ± 1.2-week intervals. The masked reviewers' grading scores demonstrated a significant improvement (2.81 ± 1.3 before vs. 1.6 ± 1.1 after, p < 0.001). The self-reported disturbance caused by the festoons improved significantly as well (4.7 ± 0.98 vs. 1.7 ± 1.1, p < 0.001). On the PGIC score, 85% (17/20) reported moderate (grade 5) to significant (grade 7) improvement of symptoms and life quality after treatment. Improvement onset was reported to occur 11.2 ± 6.6 days after the first treatment (range 2-30 days), and 90% (18/20) of the patients reported improvement lasting at least 4 months after completion of the second treatment. CONCLUSIONS: Topical tetracycline application following Tixel treatment induced significant improvement in patient with festoons.

Polymeric Microneedles for Health Care Monitoring: An Emerging Trend.

Bioanalyte collection by blood draw is a painful process, prone to needle phobia and injuries. Microneedles can be engineered to penetrate the epidermal skin barrier and collect analytes from the interstitial fluid, arising as a safe, painless, and effective alternative to hypodermic needles. Although there are plenty of reviews on the various types of microneedles and their use as drug delivery systems, there is a lack of systematization on the application of polymeric microneedles for diagnosis. In this review, we focus on the current state of the art of this field, while providing information on safety, preclinical and clinical trials, and market distribution, to outline what we believe will be the future of health monitoring.

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

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

Rapid Correction of the Hypoglycemia State in Nonhuman Primates Using a Glucagon Long-Dissolving Microneedle Patch.

The timely administration of glucagon is a standard clinical practice for the treatment of severe hypoglycemia. However, the process involves cumbersome steps, including the reconstitution of labile glucagon and filling of the syringe, which cause considerable delays in emergency situations. Moreover, multiple dosages are often required to prevent the recurrence of the hypoglycemic episode because of the short half-life of glucagon in plasma. Herein, we develop a glucagon-loaded long-dissolving microneedle (GLMN) patch that exhibits the properties of fast onset and sustained activity for the effective treatment of severe hypoglycemia. Three types of MN patches were fabricated with different dimensions (long, medium, and short). The longer MN patch packaged a higher dosage of glucagon and exhibited supreme mechanical strength compared to the shorter one. Additionally, the longer MN patch could insert more deeply into the skin, resulting in higher permeability of glucagon across the skin tissue and more rapid systemic absorption as compared with the shorter MN patch. The GLMN patch was observed to reverse the effects of hypoglycemia within 15 min of application in animal models (specifically, rat and rhesus monkey models) and maintained long-term glycemic control, owing to highly efficient drug permeation and the drug reservoir effect of the MN base. The current study presents a promising strategy for the rapid reversal of severe hypoglycemia that exhibits the desirable properties of easy use, high efficiency, and sustained action.

Fabrication and mechanical modelling of dissolvable PVA/PVP composite microneedles with biocompatibility for efficient transdermal delivery of ibuprofen.

Microneedles offer minimally invasive, user-friendly, and subcutaneously accessible transdermal drug delivery and have been widely investigated as an effective transdermal delivery system. Ibuprofen is a common anti-inflammatory drug to treat chronic inflammation. It is crucial to develop microneedle patches capable of efficiently delivering ibuprofen through the skin for the effective treatment of arthritis patients requiring repeated medication. In this study, the mechanical properties of a new type of polymer microneedle were studied by finite element analysis, and the experimental results showed that the microneedle could effectively deliver drugs through the skin. In addition, a high ibuprofen-loaded microneedle patch was successfully prepared by micromolding and subjected to evaluation of its infrared spectrum morphology and dissolve degree. The morphology of microneedles was characterized by scanning electron microscopy, and the mechanical properties were assessed using a built linear stretching system. In the in-vitro diffusion cell drug release test, the microneedle released 85.2 ± 1.52% (210 ± 3.7 µg) ibuprofen in the modified Franz diffusion within 4 h, exhibiting a higher drug release compared to other drug delivery methods. This study provides a portable, safe and efficient treatment approach for arthritis patients requiring daily repeated medication.