Lidocaine-loaded dissolving microneedle for safe local anesthesia on oral mucosa for dental procedure.

BACKGROUND: Lidocaine has been widely used as a short-acting local anesthetic agent to reduce the pain caused by needle insertion. Dissolving microneedles (DMNs), which are minimally invasive, can effectively deliver drugs by overcoming the oral mucosal barrier and relieving patient discomfort. METHODS: Lidocaine solution prepared by mixing lidocaine-HCl and hyaluronic acid was used to fabricate oral lidocaine HCl-encapsulated DMNs (oral Li-DMNs) via centrifugal lithography. The dissolution, penetration ability, and local transmucosal drug delivery of oral Li-DMNs into the oral mucosa were evaluated in porcine jaws. Pharmacokinetic analysis and safety assessment were performed using rabbits. RESULTS: The insertion depth of the oral Li-DMNs satisfies the safety standard. The oral Li-DMNs were completely dissolved after 3 min of application. The local transmucosal drug delivery, pharmacokinetic, and safety evaluations showed that the oral Li-DMNs can obtain a local anesthesia effect at a relatively lower dose, and there was no oral mucosal irritation in rabbits. CONCLUSIONS: A novel and safe oral Li-DMNs have potential applications in large animals and clinical trials and would possibly enter the anesthesia market.

Fabrication of liraglutide-encapsulated triple layer hyaluronic acid microneedles (TLMs) for the treatment of obesity.

Obesity is a chronic metabolic disease that is prevalent worldwide, causing complications that affect the quality of life and longevity of humans. Currently, the low bioavailability upon subcutaneous injection of an appetite suppressant, liraglutide, and health problems in the locally injected region remain to be overcome. In this study, we developed a novel hyaluronic acid-based liraglutide-encapsulated triple-layer microneedle (TLM) as a painless and patient-friendly long-term drug delivery system. In contrast to previous anti-obesity microneedle approaches, this TLM is composed of three layers for complete skin insertion, protecting the encapsulated liraglutide from environmental stresses. Daily topical application of the liraglutide-loaded TLM significantly reduced body weight and improved body composition in a mouse model of high-fat diet-induced obesity. Additionally, it ameliorated diet-induced hepatic steatosis in obese mice. This novel TLM could promote a glucagon-like peptide-1 drug release system for long-term daily administration with relatively higher patient compliance compared to subcutaneous injection.

Egg Microneedle for Transdermal Delivery of Active Liraglutide.

Liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, is promising for safely treating type 2 diabetes mellitus (T2DM), compared to insulin, by significantly reducing the risk of glucose-dependent hypoglycemia. Concerns related to injection prevent T2DM patients from taking liraglutide regularly, even though once-a-day subcutaneous (SC) injections. Dissolving microneedles (DMNs) are promising substitutes for SC injection and for improving patient convenience. However, there are two fundamental limitations: the low drug delivery due to incomplete insertion and loss of drug activity during DMN fabrication. Here, it is shown that an egg microneedle (EMN) designed with three functional layered structures can maintain the maximum activity of the loaded compound during DMN fabrication and deliver it completely into the skin, with the base layer allowing the complete delivery of liraglutide, and the shell layer maintaining the drug activity by mimicking the role of albumin in eggs. In a diabetic mouse model, liraglutide administration via EMN exhibited similar effect when compared to that of injection. Therefore, EMN-mediated liraglutide administration is a good potential option for replacing liraglutide injections in T2DM treatment.

Shape of dissolving microneedles determines skin penetration ability and efficacy of drug delivery.

Dissolving microneedles (DMNs) are used for minimally invasive transdermal drug delivery. Dissolution of drugs is achieved in the body after skin penetration by DMNs. Unlike injections, the insertion depth of the DMN is an important issue because the amount of dissolved DMN in the skin determines the amount of drug delivered. Therefore, the inaccurate drug delivery due to the incomplete insertion is one of the limitations of the DMN. Thus, many insertion and penetration tests have been essentially conducted in DMN studies, yet only incomplete insertion is known and the exact standard for how much it is not inserted is still unknown. Moreover, there are various shapes have been introduced in the microneedle field, there have been only few studies that have compared and evaluated the insertion depth of the shapes. Here, we present an intensive approach for DMN insertion based on DMN shape among various insertion deciding factors. We numerically analyzed the volumetric distribution of three types of DMN shapes: conical-shaped DMN, funnel-shaped DMN, and candlelit-shaped DMN, and introduced a new insertion evaluation criterion while covering previous insertion evaluations. Using optical coherence tomography, the images of DMNs embedded in the skin were analyzed in rea l-time, and the amount of drug delivered was analyzed at sectioned depth with a cryotome. The in vitro data confirmed that the insertion depth differed based on shape, and the resulting drug delivery depended on the volume assigned to the insertion depth. Insulin-loaded DMNs were applied to C57BL/6 mice, and the results of pharmacokinetic and pharmacodynamic analyses supported the results of the in vitro analysis. Our approach, which considers the correlation between DMN shape and insertion depth, will contribute to establishing criteria for various DMN design and maximizing drug delivery.

Enhanced Micro-Channeling System via Dissolving Microneedle to Improve Transdermal Serum Delivery for Various Clinical Skincare Treatments.

Topical liquid formulations, dissolving microneedles (DMNs), and microscale needles composed of biodegradable materials have been widely used for the transdermal delivery of active compounds for skincare. However, transdermal active compound delivery by topical liquid formulation application is inhibited by skin barriers, and the skincare efficacy of DMNs is restricted by the low encapsulation capacity and incomplete insertion. In this study, topical serum application via a dissolvable micro-channeling system (DMCS) was used to enhance serum delivery through micro-channels embedded with DMNs. Transdermal serum delivery was evaluated after the topical-serum-only application and combinatorial serum application by assessing the intensity of allophycocyanin (APC) loaded with the serum in the porcine skin. APC intensity was significantly higher in the skin layer at a depth of 120-270 µm upon combinatorial serum application as compared to topical-serum-only application. In addition, the combinatorial serum application showed significantly improved efficacy in the clinical assessment of skin hydration, depigmentation, improvement of wrinkles, elasticity, dermal density, skin pores, and skin soothing without any safety issues compared to the serum-only application. The results indicate that combinatorial serum application with DMCS is a promising candidate for improving skincare treatments with optimal transdermal delivery of active compounds.

Development of Clinical Weekly-Dose Teriparatide Acetate Encapsulated Dissolving Microneedle Patch for Efficient Treatment of Osteoporosis.

Teriparatide acetate (TA), which directly promotes bone formation, is subcutaneously injected to treat osteoporosis. In this study, TA with a once-weekly administration regimen was loaded on dissolving microneedles (DMNs) to effectively deliver it to the systemic circulation via the transdermal route. TA activity reduction during the drying process of various TA polymer solutions formulated with hyaluronic acid and trehalose was monitored and homogeneities were assessed. TA-DMN patches fabricated using centrifugal lithography in a two-layered structure with dried pure hyaluronic acid on the base layer and dried TA polymer solution on the top layer were evaluated for their physical properties. Rhodamine-B-loaded TA-DMNs were found to form perforations when inserted into porcine skin using a shooting device. In addition, 87.6% of TA was delivered to the porcine skin after a 5-min TA-DMN patch application. The relative bioavailability of TA via subcutaneous injection was 66.9% in rats treated with TA-DMN patches. The maximal TA concentration in rat plasma was proportional to the number of patches used. Therefore, the TA-DMN patch fabricated in this study may aid in the effective delivery of TA in a patient-friendly manner and enhance medical efficacy in osteoporosis treatment.

Technical Consideration towards Robust 3D Reconstruction with Multi-View Active Stereo Sensors.

It is possible to construct cost-efficient three-dimensional (3D) or four-dimensional (4D) scanning systems using multiple affordable off-the-shelf RGB-D sensors to produce high-quality reconstructions of 3D objects. However, the quality of these systems' reconstructions is sensitive to a number of factors in reconstruction pipelines, such as multi-view calibration, depth estimation, 3D reconstruction, and color mapping accuracy, because the successive pipelines to reconstruct 3D meshes from multiple active stereo sensors are strongly correlated with each other. This paper categorizes the pipelines into sub-procedures and analyze various factors that can significantly affect reconstruction quality. Thus, this paper provides analytical and practical guidelines for high-quality 3D reconstructions with off-the-shelf sensors. For each sub-procedure, this paper shows comparisons and evaluations of several methods using data captured by 18 RGB-D sensors and provide analyses and discussions towards robust 3D reconstruction. Through various experiments, it has been demonstrated that significantly more accurate 3D scans can be obtained with the considerations along the pipelines. We believe our analyses, benchmarks, and guidelines will help anyone build their own studio and their further research for 3D reconstruction.

A Comparison and Evaluation of Stereo Matching on Active Stereo Images.

The relationship between the disparity and depth information of corresponding pixels is inversely proportional. Thus, in order to accurately estimate depth from stereo vision, it is important to obtain accurate disparity maps, which encode the difference between horizontal coordinates of corresponding image points. Stereo vision can be classified as either passive or active. Active stereo vision generates pattern texture, which passive stereo vision does not have, on the image to fill the textureless regions. In passive stereo vision, many surveys have discovered that disparity accuracy is heavily reliant on attributes, such as radiometric variation and color variation, and have found the best-performing conditions. However, in active stereo matching, the accuracy of the disparity map is influenced not only by those affecting the passive stereo technique, but also by the attributes of the generated pattern textures. Therefore, in this paper, we analyze and evaluate the relationship between the performance of the active stereo technique and the attributes of pattern texture. When evaluating, experiments are conducted under various settings, such as changing the pattern intensity, pattern contrast, number of pattern dots, and global gain, that may affect the overall performance of the active stereo matching technique. Through this evaluation, our discovery can act as a noteworthy reference for constructing an active stereo system.

Multiple Sensor Synchronization with theRealSense RGB-D Camera.

When reconstructing a 3D object, it is difficult to obtain accurate 3D geometric information using a single camera. In order to capture detailed geometric information of a 3D object, it is inevitable to increase the number of cameras to capture the object. However, cameras need to be synchronized in order to simultaneously capture frames. If cameras are incorrectly synchronized, many artifacts are produced in the reconstructed 3D object. The RealSense RGB-D camera, which is commonly used for obtaining geometric information of a 3D object, provides synchronization modes to mitigate synchronization errors. However, the synchronization modes provided by theRealSense cameras can only sync depth cameras and have limitations in the number of cameras that can be synchronized using a single host due to the hardware issue of stable data transmission. Therefore, in this paper, we propose a novel synchronization method that synchronizes an arbitrary number of RealSense cameras by adjusting the number of hosts to support stable data transmission. Our method establishes a master-slave architecture in order to synchronize the system clocks of the hosts. While synchronizing the system clocks, delays that resulted from the process of synchronization were estimated so that the difference between the system clocks could be minimized. Through synchronization of the system clocks, cameras connected to the different hosts can be synchronized based on the timestamp of the data received by the hosts. Thus, our method synchronizes theRealSense cameras to simultaneously capture accurate 3D information of an object at a constant frame rate without dropping it.

Optimization of Layered Dissolving Microneedle for Sustained Drug Delivery Using Heat-Melted Poly(Lactic-Co-glycolic Acid).

Dissolving microneedles (DMNs) have been used as an alternative drug delivery system to deliver therapeutics across the skin barrier in a painless manner. In this study, we propose a novel heat-melting method for the fabrication of hydrophobic poly(lactic-co-glycolic acid) (PLGA) DMNs, without the use of potentially harmful organic solvents. The drug-loaded PLGA mixture, which consisted of a middle layer of the DMN, was optimized and successfully implanted into ex vivo porcine skin. Implanted HMP-DMNs separated from the patch within 10 min, enhancing user compliance, and the encapsulated molecules were released for nearly 4 weeks thereafter. In conclusion, the geometry of HMP-DMNs was successfully optimized for safe and effective transdermal sustained drug delivery without the use of organic solvents. This study provides a strategy for the innovative utilization of PLGA as a material for transdermal drug delivery systems.

Dissolving Candlelit Microneedle for Chronic Inflammatory Skin Diseases.

Chronic inflammatory skin diseases (CISDs) negatively impact a large number of patients. Injection of triamcinolone acetonide (TA), an anti-inflammatory steroid drug, directly into the dermis of diseased skin using needle-syringe systems is a long-established procedure for treating recalcitrant lichenified lesions of CISDs, referred to as TA intralesional injection (TAILI). However, TAILI causes severe pain, causing patients to be stressed and reluctant to undergo treatment. Furthermore, the practitioner dependency on the amount and depth of the injected TA makes it difficult to predict the prognosis. Here, candle flame ("candlelit")-shaped TA-loaded dissolving microneedles (Candlelit-DMN) are designed and fabricated out of biocompatible and biodegradable molecules. Candlelit-DMN distributes TA evenly across human skin tissue. Conjoined with the applicator, Candlelit-DMN is efficiently inserted into human skin in a standardized manner, enabling TA to be delivered within the target layer. In an in vivo skin inflammation mouse model, Candlelit-DMN inserted with the applicator effectively alleviates inflammation by suppressing inflammatory cell infiltration and cytokine gene expression, to the same extent as TAILI. This Candlelit-DMN with the applicator arouses the interest of dermatologists, who prefer it to the current TAILI procedure.

High-Dose Steroid Dissolving Microneedle for Relieving Atopic Dermatitis.

Dissolving microneedles (DMN) supplemented with therapeutic molecules have been developed to enhance transdermal delivery efficiency of topically applied drugs in a minimally invasive manner. However, the dose of the drugs in DMN system is limited owing to the low solubility of drug. In fact, although triamcinolone acetonide (TA) is one of the most widely prescribed drugs for relieving atopic dermatitis (AD), its poor dissolving nature makes it difficult to design and fabricate DMN containing therapeutic dosage of TA. In this study, TA suspension is introduced to encapsulate therapeutic dosage of TA. Sonication and composition optimization of polymers is key to fabricate high dose TA-DMN to induce particle size reduction and dispersion stability of suspension, respectively. After confirming the physical performance of TA-DMN using the selected formulation in vitro, the anti-inflammatory effects of TA-DMN are evaluated in vivo using a mouse model affected with skin inflammation to mimic AD in humans. Herein, high-dose TA-DMN is presented as a candidate agent for relieving AD and, furthermore, for wide application in the treatment of skin inflammatory diseases in which high-dose steroid drugs are required.

Development of Lidocaine-Loaded Dissolving Microneedle for Rapid and Efficient Local Anesthesia.

Lidocaine is a local anesthetic agent used in the form of injection and topical cream. However, these formulation types have limitations of being either painful or slow-acting, thereby hindering effective and complete clinical performance of lidocaine. Dissolving microneedles (DMNs) are used to overcome these limitations owing to their fast onset time and minimally invasive administration methods. Using hyaluronic acid and lidocaine to produce the drug solution, a lidocaine HCl encapsulated DMN (Li-DMN) was fabricated by centrifugal lithography. The drug delivery rate and local anesthetic quality of Li-DMNs were evaluated using the pig cadaver insertion test and Von Frey behavior test. Results showed that Li-DMNs could deliver sufficient lidocaine for anesthesia that is required to be utilized for clinical level. Results from the von Frey test showed that the anesthetic effect of Li-DMNs was observed within 10 min after administration, thus confirming fast onset time. A toxicity test for appropriate clinical application standard was conducted with a microbial limit test and an animal skin irritation test, showing absence of skin irritation and irritation-related microorganisms. Overall, Li-DMN is a possible alternative drug delivery method for local anesthesia, meeting the requirements for clinical conditions and overcoming the drawbacks of other conventional lidocaine administration methods.

Micro-Pillar Integrated Dissolving Microneedles for Enhanced Transdermal Drug Delivery.

The dissolving microneedle (DMN) patch is a transdermal delivery system, containing arrays of micro-sized polymeric needles capable of encapsulating therapeutic drugs within their matrix and releasing them into the skin. However, the elastic properties of the skin prevent DMNs from complete insertion and accurate delivery of encapsulated compounds into the skin. Moreover, the adhesive materials used in patches may cause skin irritation, inflammation, and redness. Therefore, we developed a patchless, micro-pillar integrated DMN (P-DMN) that is simple to fabricate and enhances transdermal drug delivery compared with traditional DMN patches. The micro-pillars were made of polymethyl methacrylate at a height of 300 µm and a base diameter of 500 µm. To fabricate P-DMNs, we employed hyaluronic acid, which is a widely used derma filler and plays a role in tissue re-epithelialization. We demonstrate that utilizing P-DMNs significantly improves the delivery efficiency of an encapsulated drug surrogate (91.83% ± 7.75%) compared with traditional DMNs (64.86% ± 8.17%). Interestingly, P-DMNs remarkably increase the skin penetration accuracy rate of encapsulated drugs, up to 97.78% ± 2.22%, compared with 44.44% ± 7.85% in traditional DMNs. Our findings suggest that P-DMNs could serve as a highly accurate and efficient platform for transdermal delivery of various types of micro- and macro-biomolecules.

Two-phase delivery using a horse oil and adenosine-loaded dissolving microneedle patch for skin barrier restoration, moisturization, and wrinkle improvement.

BACKGROUND: Dissolving microneedles (DMNs) have been used for skin restoration and wrinkle improvement. Although lipophilic compounds, for example, natural oils or ceramides, enrich the skin barrier, their delivery via DMNs is challenging because of DMN fabrication difficulties. OBJECTIVES: In the present study, we combined a topical formulation and a DMN patch to perform two-phase delivery comprising a lipophilic formulation and hydrophilic compound-loaded DMNs to improve skin barrier status and the efficacy of drug delivery. METHODS: Horse oil-spread and adenosine-loaded DMN arrays were developed in a single patch (HOS-Ad-DMN patch). In vitro analysis was conducted to confirm the successful delivery of the compositions. Clinical assessments were conducted on the lateral canthus of 20 women to compare the efficacy of HOS-Ad-DMN patches with that of adenosine-loaded DMN patches (Ad-DMN patches). RESULTS: Adenosine was delivered via the DMNs after skin penetration and horse oil was delivered successfully into the skin through the microchannels created by the Ad-DMNs. Compared with Ad-DMN patches, HOS-Ad-DMN patches significantly improved skin elasticity, hydration, dermal density, and wrinkles. No adverse events were observed. CONCLUSION: HOS-Ad-DMN patches are a safe and efficient system for skin restoration and wrinkle improvement.

Combinatorial application of dissolving microneedle patch and cream for improvement of skin wrinkles, dermal density, elasticity, and hydration.

BACKGROUND: Dissolving microneedles (DMNs), microscale needles with a biodegradable polymer matrix, have been widely investigated for transdermal drug delivery. However, the restricted drug loading space of DMNs limited the delivery of the desired quantity of active compounds. In this study, we developed novel combinatorial therapies involving sequential application of adenosine-loaded DMN (Ad-DMN) patches and a topical adenosine-loaded cream (Ad-cream). The application of DMNs created skin channels, which delivered encapsulated drugs from both the DMNs and cream. The use of combinatorial therapies can maximize drug delivery. METHODS: To compare the efficacy of combinatorial therapies and Ad-cream application, a double-blind clinical test was conducted over 10 weeks on 21 females with wrinkles around their eyes, and the skin parameters such as wrinkles, dermal density, elasticity, and hydration were analyzed. The skin irritation test was assessed by expert interviewers to elucidate undesirable side effects. RESULTS: The combinatorial therapies showed statistically significant efficacy for the improvement of average depth of wrinkles, dermal density, elasticity, and hydration after an 8-week application (P < 0.001). Adverse effects on the skin were not observed in any subject during the test period. CONCLUSION: The efficacy and safety results showed that the combinatorial therapies were a safe and outstanding innovation for the optimization of transdermal therapy.

Skin Barrier Restoration and Moisturization Using Horse Oil-Loaded Dissolving Microneedle Patches.

BACKGROUND: Horse oil (HO) has skin barrier restoration and skin-moisturizing effects. Although cream formulations have been used widely and safely, their limited penetration through the stratum corneum is a major obstacle to maximizing the cosmetic efficacy of HO. Therefore, we aimed to encapsulate HO in a cosmetic dissolving microneedle (DMN) for efficient transdermal delivery. METHODS: To overcome these limitations of skin permeation, HO-loaded DMN (HO-DMN) patches were developed and evaluated for their efficacy and safety using in vitro and clinical studies. RESULTS: Despite the lipophilic nature of HO, the HO-DMN patches had a sharp shape and uniform array, with an average length and tip diameter of 388.36 ± 16.73 and 38.54 ± 5.29 µm, respectively. The mechanical strength of the HO-DMN patches was sufficient (fracture force of 0.29 ± 0.01 N), and they could successfully penetrate pig skin. During the 4-week clinical evaluation, HO-DMN patches caused significant improvements in skin and dermal density, skin elasticity, and moisturization. Additionally, a brief safety assessment showed that the HO-DMN patches induced negligible adverse events. CONCLUSION: The HO-DMNs are efficient, safe, and convenient for wide use in cosmetic applications for skin barrier restoration and moisturization.

Effects of dissolving microneedle fabrication parameters on the activity of encapsulated lysozyme.

Dissolving microneedle (DMN) is referred to a microscale needle that encapsulates drug(s) within a biodegradable polymer matrix and delivers it into the skin in a minimally invasive manner. Although vast majority of studies have emphasized DMN as an efficient drug delivery system, the activity of DMN-encapsulated proteins or antigens can be significantly affected due to a series of thermal, physical and chemical stress factors during DMN fabrication process and storage period. The objective of this study is to evaluate the effects of DMN fabrication parameters including polymer type, polymer concentration, fabrication and storage temperature, and drying conditions on the activity of the encapsulated therapeutic proteins by employing lysozyme (LYS) as a model protein. Our results indicate that a combination of low temperature fabrication, mild drying condition, specific polymer concentration, and addition of protein stabilizer can maintain the activity of encapsulated LYS up to 99.8 ±â€¯3.8%. Overall, findings of this study highlight the importance of optimizing DMN fabrication parameters and paves way for the commercialization of an efficient delivery system for therapeutics.

Exendin-4-encapsulated dissolving microneedle arrays for efficient treatment of type 2 diabetes.

Dissolving microneedles (DMNs) are microscopic needles capable of delivering encapsulated compounds and releasing them into the skin in a minimally invasive manner. Most studies indicate that encapsulating therapeutics in DMNs is an efficacious approach; however, the importance of evaluating the activity of encapsulated compounds, during the fabrication process, has not been examined in detail. Conducting an analysis of thermal, chemical, and physical stress factors, including temperature, pH, and the interaction of the polymer and therapeutics mixture during preparation, is essential for retaining the activity of encapsulated therapeutics during and after fabrication. Here, we optimised the thermal, chemical, and physical parameters for the fabrication of exendin-4 (Ex-4)-encapsulated DMNs (Ex-4 DMNs). Ex-4, a peptide agonist of glucagon-like peptide (GLP) receptor, is used for glycaemic control in patients with type 2 diabetes. Our findings indicate that optimising the parameters involved in DMN fabrication retained the activity of Ex-4 by up to 98.3 ± 1.5%. Ex-4 DMNs reduced the blood-glucose level in diabetic mice with efficiency similar to that of a subcutaneous injection. We believe that this study paves way for the commercialisation of an efficient and minimally invasive treatment for patients with type 2 diabetes.

Effects of two droplet-based dissolving microneedle manufacturing methods on the activity of encapsulated epidermal growth factor and ascorbic acid.

Dissolving microneedle (DMN) is an attractive, minimally invasive transdermal drug delivery technology. The drugs encapsulated in the DMNs are exposed to a series of thermal, chemical, and physical stresses during the fabrication process, decreasing their therapeutic activity. Current DMN fabrication methods, such as micro-molding, drawing lithography, droplet-born air blowing, and centrifugal lithography, undergo different manufacturing processes involving differing stress conditions. Among the methods, we compared the effects of two droplet-based methods, droplet-born air blowing and centrifugal lithography, on the activity of encapsulated drugs using epidermal growth factor and ascorbic acid as model drugs. Although the appearance and physical properties of DMNs fabricated by the two methods were similar, the immunoreactivity of encapsulated epidermal growth factor in centrifugal lithography and droplet-born air blowing was 92.08±2.86% and 80.67±8.00%, respectively, at baseline, and decreased to 75.32±19.40% and 41.75±16.17%, respectively, 24h after drug-loading. The free-radical scavenging activity of ascorbic acid was maintained at 88.24±0.78% in DMNs fabricated by centrifugal lithography, but decreased over time to 67.02±1.11% in DMNs fabricated by droplet-born air blowing. These findings indicate that the manufacturing conditions of centrifugal lithography exert less stress on the drug-loaded DMNs, minimizing activity loss over time, and therefore that centrifugal lithography is suitable for fabricating DMNs loaded with fragile biological drugs.