Astragalus membranaceus(Fisch.)Bge.administered by dissolving microneedles achieves systemic therapeutic effects at low doses Author links open overlay panel

Objective To determine the main components of Astragalus membranaceus(Fisch.)Bge(A.membranaceus,Huang Qi),Astragaloside IV(AIV)and Astragalus polysaccharides(AP),to characterize their properties,evaluate their in vivo efficacy,and to analyze drug diffusion using dissolving microneedle(DMN)technology in vivo.Methods Respectively,AIV-and AP-loaded DMNs comprising chitosan(CTS)and polyvinyl alcohol(PVA)were prepared via dual-mold forming.Their morphology,mechanical properties,in vivo solubility,and skin irritation characteristics were tested.In vivo efficacy was assessed in cyclophosphamide-induced immunosuppressed mice,in vivo diffusion of AIV and AP by DMNs and conventional methods was compared,and the rheological properties of AIV-CTS-PVA and AP-CTS-PVA mixtures were measured.Results Subcutaneous dissolution and absorption of AIV-CTS-PVA and AP-CTS-PVA microneedles(MNs)at low doses(50%–17%of intraperitoneal AIV injection and 12%–4%of intravenous AP injection)reduced the spleen index and acid phosphatase activity in immunosuppressed mouse models,increased the thymus index,and achieved equivalent or better systemic therapeutic effects.Compared with injections,AIV and AP achieved controllable solid-liquid conversion through delivery with CTS-PVA MNs,resulting in highly localized aggregation within 48 h,reducing the initial explosive effect of the drug,and achieving stable and slow drug release.Conclusion The present study enhances our understanding of the efficacy and remote effects of drug-loaded DMNs from a traditional Chinese medicine(TCM)perspective,thereby promoting the development of precise and efficient delivery of TCM and further expanding the drug-loading range and application scenarios for DMNs.

Microneedles for Enhanced Topical Treatment of Skin Disorders:Applications,Challenges,and Prospects

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

Dissolvable polymeric microneedles loaded with aspirin for antiplatelet aggregation

To reduce mucosal damage in the gastrointestinal tract caused by aspirin,we developed a dissolvable polymeric microneedle(MN)patch loaded with aspirin.Biodegradable polymers provide mechanical strength to the MNs.The MN tips punctured the cuticle of the skin and dissolved when in contact with the subcutaneous tissue.The aspirin in the MN patch is delivered continuously through an array of micropores created by the punctures,providing a stable plasma concentration of aspirin.The factors affecting the stability of aspirin during MNs fabrication were comprehensively analyzed,and the hydrolysis rate of aspirin in the MNs was less than 2%.Compared to oral administration,MN administration not only had a smoother plasma concentration curve but also resulted in a lower effective dose of antiplatelet aggregation.Aspirin-loaded MNs were mildly irritating to the skin,causing only slight erythema on the skin and recovery within 24 h.In summary,aspirin-loaded MNs provide a new method to reduce gastrointestinal adverse effects in patients requiring aspirin regularly.

Revolutionizing diabetic wound healing:The power of microneedles

Diabetic wounds significantly affect patient quality of life.Microneedles are a promising treatment to accelerate wound healing owing to their high drug-loading capacity and efficient drug delivery;however,few studies to date have comprehensively reviewed microneedles for diabetic wound healing.This up-to-date review summarizes the research progress in microneedles for diabetic wound healing,including manufacturing materials and techniques,structures,designs,release mechanisms,delivery substances,and their specific effects.This study showed that most microneedles designed for diabetic wounds are made of synthetic polymers and/or natural materials using polydimethylsiloxane micromolding.The geometric structure and design directly influence penetration ability and drug delivery capacity.Microneedles can deliver antibiotics,hypoglycemic agents,traditional Chinese medicines,metal ions,growth factors,exosomes,stem cells,and microorganisms,thus promoting diabetic wound healing through diverse mechanisms,such as antibacterial,anti-inflammatory,antioxidant,hypoglycemic,and angiogenic activities,at different stages of the healing process.In conclusion,microneedles are promising drug delivery systems for the treatment of diabetic wounds.

Development, Application and Prospect of Dissolving Microneedles

In recent years, as a new transdermal drug delivery method, microneedle transdermal drug delivery technology accelerates the absorption of drugs through micron pores, which has been widely used in the field of medicine and cosmetics. Dissolving microneedles have the characteristics of good biocompatibility and fast dissolution speed, which attract more and more researchers’ attention and research. In this paper, the concept, properties and preparation methods of dissolving microneedles as well as the research status of dissolving microneedles in the field of medicine and cosmetics in recent years were summarized and prospected, so as to enable researchers to have a clearer and comprehensive understanding of dissolving microneedles and prospect the application and development prospects of dissolving microneedles in the industry.

Advances in Polysaccharide-Based Microneedle Systems for the Treatment of Ocular Diseases

The eye,a complex organ isolated from the systemic circulation,presents significant drug delivery challenges owing to its protective mechanisms,such as the blood-retinal barrier and corneal impermeability.Conventional drug administration methods often fail to sustain therapeutic levels and may compromise patient safety and compliance.Polysaccharidebased microneedles(PSMNs)have emerged as a transformative solution for ophthalmic drug delivery.However,a comprehensive review of PSMNs in ophthalmology has not been published to date.In this review,we critically examine the synergy between polysaccharide chemistry and microneedle technology for enhancing ocular drug delivery.We provide a thorough analysis of PSMNs,summarizing the design principles,fabrication processes,and challenges addressed during fabrication,including improving patient comfort and compliance.We also describe recent advances and the performance of various PSMNs in both research and clinical scenarios.Finally,we review the current regulatory frameworks and market barriers that are relevant to the clinical and commercial advancement of PSMNs and provide a final perspective on this research area.

Flexible capacitive pressure sensor based on interdigital electrodes with porous microneedle arrays for physiological signal monitoring

Flexible pressure sensors have many potential applications in the monitoring of physiological signals because of their good biocompatibil-ity and wearability.However,their relatively low sensitivity,linearity,and stability have hindered their large-scale commercial application.Herein,aflexible capacitive pressure sensor based on an interdigital electrode structure with two porous microneedle arrays(MNAs)is pro-posed.The porous substrate that constitutes the MNA is a mixed product of polydimethylsiloxane and NaHCO3.Due to its porous and interdigital structure,the maximum sensitivity(0.07 kPa-1)of a porous MNA-based pressure sensor was found to be seven times higher than that of an imporous MNA pressure sensor,and it was much greater than that of aflat pressure sensor without a porous MNA structure.Finite-element analysis showed that the interdigital MNA structure can greatly increase the strain and improve the sensitivity of the sen-sor.In addition,the porous MNA-based pressure sensor was found to have good stability over 1500 loading cycles as a result of its bilayer parylene-enhanced conductive electrode structure.Most importantly,it was found that the sensor could accurately monitor the motion of afinger,wrist joint,arm,face,abdomen,eye,and Adam’s apple.Furthermore,preliminary semantic recognition was achieved by monitoring the movement of the Adam’s apple.Finally,multiple pressure sensors were integrated into a 33 array to detect a spatial pressure distribu-×tion.Compared to the sensors reported in previous works,the interdigital electrode structure presented in this work improves sensitivity and stability by modifying the electrode layer rather than the dielectric layer.

Ultra-precision positioning control technique based on neural network

Due to the non-linearity behavior of the precision positioning system, an accurate mathematical control model is difficult to set up, a novel control method for ultra-precision alignment is presented. This method relies on neural network and alignment marks that are in the form of 100μm pitch gratings. The 0-th order Moire signals＇ intensity and its intensity rate are chosen as input variables of the neural network. The characteristics of the neural network make it possible to perform self-training and self-adjusting so as to achieve automatic precision alignment. A neural network model for precision positioning is set up. The model is composed of three neural layers, i.e. input layer, hidden layer and output layer. Driving signal is obtained by mapping Moire signals＇ intensity and its intensity rate. The experimental results show that neural network control for precision positioning can effectively improve positioning speed with high accuracy. It has the advantages of fast, stable response and good robustness. The device based on neural network can achieve the positioning accuracy of ± 0. 5μm.

Ultra-precision alignment technique based on modified Moiré signals

A novel method for automatic ultra-precision alignment is presented.This method relies on the modified Moiré technique,and alignment marks are used in the form of gratings.The modified Moiré technique can effectively improve detecting sensitivity of signals and simplify the control system by using only one pair of laser-Moiré sensors.We present the mathematical model and simulation results of diffracting two gratings.The effect of various parameters on Moiré signals is studied theoretically and experimentally,and the results are found to be consistent.A computer controlled alignment device using one pair of Moiré sensors is designed.The device can achieve a fully automatic precision alignment by the modified Moiré signal.The experimental result shows that the alignment device can obtain the resolution of 5 nm and the positioning accuracy of ±0 5 μm.

Fabrication of gelatin methacryloyl hydrogel microneedles for transdermal delivery of metformin in diabetic rats

Injection therapy for diabetes has poor patient compliance,and the pain occurring at the site of subcutaneous injections causes significant inconvenience to diabetic patients.In this work,to demonstrate the benefits of an alternative drug delivery technique that overcomes these issues,methacrylated gelatin hydrogel-forming microneedles integrated with metformin were developed to adjust blood glucose levels in diabetic rats.Gelatin methacryloyl microneedles(GelMA-MNs)with different degrees of substitution were successfully prepared by a micro-molding method.The resultant GelMA-MNs exhibited excellent mechanical properties and moisture resistance.Metformin,an anti-diabetic drug,was further encapsulated into the GelMA-MNs,and its release rate could be controlled by the three-dimensional cross-linked network of microneedles,thereby exhibiting sustained drug release behaviors in vitro and implying a better therapeutic effect compared with that of subcutaneous injection in diabetic rats.The drug release period could be significantly prolonged by improving the cross-link density of GelMA-MNs.The results of hypoglycemic effect evaluation show that the application of GelMA-MNs for transdermal delivery in diabetic rats has promising benefits for diabetes treatment.

INFLUENCE OF WHEEL STRUCTURAL PARAMETERS ON MACHINING ACCURACY OF ULTRA-PRECISION PLANE HONING

A new idea for designing wheel patterns is presented so as to solve theproblems about machining accuracy of workpiece and wear of honing wheel in ultra-precision planehoning. The influence factors on motion principle and pattern structures are analyzed andoptimization machining parameters are obtained. By calculating effective cutting length on thesurface of workpiece cut by wheel's abrasive and the orbit of one point on the surface of workpiececontacting with wheel, the wear coefficient of different kinds of wheels and accuracy coefficient ofworkpiece machined by corresponding wheels are obtained. Furthermore, the simulation results showthat the optimal pattern structure of wheel turns out to have lower wheel wear and higher machiningaccuracy.

Dynamic Accuracy Design Method of Ultra-precision Machine Tool

Ultra-precision machine tool is the most important physical tool to machining the workpiece with the frequency domain error requirement, in the design process of which the dynamic accuracy design(DAD) is indispensable and the related research is rarely available. In light of above reasons, a DAD method of ultra-precision machine tool is proposed in this paper, which is based on the frequency domain error allocation.The basic procedure and enabling knowledge of the DAD method is introduced. The application case of DAD method in the ultra-precision flycutting machine tool for KDP crystal machining is described to show the procedure detailedly. In this case, the KDP workpiece surface has the requirements in four different spatial frequency bands, and the emphasis for this study is put on the middle-frequency band with the PSD specifications. The results of the application case basically show the feasibility of the proposed DAD method. The DAD method of ultra-precision machine tool can effectively minimize the technical risk and improve the machining reliability of the designed machine tool. This paper will play an important role in the design and manufacture of new ultra-precision machine tool.

Systematic analysis of error sources during ultra-precision machining

During ultra-precision machining, machining accuracy is determined by many factors and interaction of these factors. Error sources are systematically analyzed for ultra-precision machine tools, and the influencing degree of each factor is presented to provide orientation for error reduction and error compensation.

Study of material removal behavior on R-plane of sapphire during ultra-precision machining based on modified slip-fracture model

In this paper, the modified slip/fracture activation model has been used in order to understand the mechanism of ductile-brittle transition on the R-plane of sapphire during ultra-precision machining by reflecting direction of resultant force. Anisotropic characteristics of crack morphology and ductility of machining depending on cutting direction were explained in detail with modified fracture cleavage and plastic deformation parameters. Through the analysis, it was concluded that crack morphologies were mainly determined by the interaction of multiple fracture systems activated while, critical depth of cut was determined by the dominant plastic deformation parameter. In addition to this, by using proportionality relationship between magnitude of resultant force and depth of cut in the ductile region, an empirical model for critical depth of cut was developed.

Enhanced delivery efficiency and sustained release of biopharmaceuticals by complexation-based gel encapsulated coated microneedles:rhIFNα-1b example

Coated microneedles(MNs) are widely used for delivering biopharmaceuticals. In this study, a novel gel encapsulated coated MNs(GEC-MNs) was developed. The water-soluble drug coating was encapsulated with sodium alginate(SA) in situ complexation gel. The manufacturing process of GEC-MNs was optimized for mass production. Compared to the water-soluble coated MNs(72.02% ± 11.49%), the drug delivery efficiency of the optimized GEC-MNs(88.42% ± 6.72%) was steadily increased, and this improvement was investigated through in vitro drug release. The sustained-release of BSA was observed in vitro permeation through the skin. The rhIFN α-1 b GEC-MNs was confirmed to achieve biosafety and 6-month storage stability. Pharmacokinetics of rhIFN α-1 b in GEC-MNs showed a linearly dosedependent relationship. The AUC of rhIFN α-1 b in GEC-MNs(4.51 ng/ml ·h) was bioequivalent to the intradermal(ID) injection(5.36 ng/ml ·h) and significantly higher than water-soluble coated MNs(3.12 ng/ml ·h). The rhIFN α-1 b elimination half-life of GEC-MNs, soluble coated MNs, and ID injection was 18.16, 1.44, and 2.53 h, respectively. The complexation-based GECMNs have proved to be more efficient, stable, and achieve the sustained-release of watersoluble drug in coating MNs, constituting a high value to biopharmaceutical.

TWO-COORDINATE DUAL-SERVO CONTOURERROR COMPENSATION TECHNOLOGY FOR ULTRA-PRECISION MANUFACTURING

A technology of two-coordinate dual-servo(TCDS) is proposed. Using this technology which is based on error compensation, workpieces of higher contour accuracy could he turned on ultra-precision machine tool with Poor dynamic performances. The principle, constitute and operation of a TCDS system are described. Mathematical proof and experiments are achieved in addition.

Transdermal delivery of fluorescein isothiocyanate-dextrans using the combination of microneedles and low-frequency sonophoresis

This study aimed to evaluate the patient-friendly methods that are used in the delivery of hydrophilic macromolecules into deep skin layers,in particular,the combination of microneedles patch(MNs patch)and low-frequency sonophoresis(SN).The hydrophilic macromolecule drug fluorescein isothiocyanate(FITC)-dextrans(FD-4:MW 4.4 kDa)was used as the model drug in our experimental design.In this study,excised porcine skin was used to investigate and optimize the key parameters that determine effective MNs-and SNfacilitated FD-4 delivery.In vitro skin permeation experiments revealed that the combination of MNs patch with SN had a superior enhancing effect of skin permeation for FD-4 compared to MNs alone,SN alone or untreated skin,respectively.The optimal parameters for the combination of MNs and SN included the following:10 N insertion force of MNs,4 W/cm^(2)SN intensity,6 mm radiation diameter of the SN probe,2 min application time,and the continuous mode duty cycle of SN.In addition,vertical sections of skin,clearly observed under a confocal microscope,confirmed that the combination of MNs and SN enhanced permeation of FD-4 into the deep skin layers.These studies suggest that the combination of MNs and SN techniques could have great potential in the delivery of hydrophilic macromolecules into deep skin.

Mesoplasticity Approach to Studies of the Cutting Mechanism in Ultra-precision Machining

There have been various theoretical attempts by researchers worldwide to link up different scales of plasticity studies from the nano-, micro- and macro-scale of observation, based on molecular dynamics, crystal plasticity and continuum mechanics. Very few attempts, however, have been reported in ultra-precision machining studies. A mesoplasticity approach advocated by Lee and Yang is adopted by the authors and is successfully applied to studies of the micro-cutting mechanisms in ultra-precision machining. Traditionally, the shear angle in metal cutting, as well as the cutting force variation, can only be determined from cutting tests. In the pioneering work of the authors, the use of mesoplasticity theory enables prediction of the fluctuation of the shear angle and micro-cutting force, shear band formation, chip morphology in diamond turning and size effect in nano-indentation. These findings are verified by experiments. The mesoplasticity formulation opens up a new direction of studies to enable how the plastic behaviour of materials and their constitutive representations in deformation processing, such as machining can be predicted, assessed and deduced from the basic properties of the materials measurable at the microscale.

Mathematical modeling of drug release from biodegradable polymeric microneedles

Transdermal drug delivery systems have overcome many limitations of other drug administration routes,such as injection pain and first-pass metabolism following oral route,although transdermal drug delivery systems are limited to drugs with low molecular weight.Hence,new emerging technology allowing high molecular weight drug delivery across the skin—known as‘microneedles’—has been developed,which creates microchannels that facilitate drug delivery.In this report,drug-loaded degradable conic microneedles are modeled to characterize the degradation rate and drug release profile.Since a lot of data are available for polylactic acid-co-glycolic acid(PLGA)degradation in the literature,PLGA of various molecular weights-as a biodegradable polymer in the polyester family-is used for modeling and verification of the drug delivery in themicroneedles.The main reaction occurring during polyester degradation is hydrolysis of steric bonds,leading to molecular weight reduction.The acid produced in the degradation has a catalytic effect on the reaction.Changes in water,acid and steric bond concentrations over time and for different radii of microneedles are investigated.To solve the partial and ordinary differential equations simultaneously,finite difference and Runge–Kutta methods are employed,respectively,with the aid of MATLAB.Correlation of the polymer degradation rate with its molecular weight and molecular weight changes versus time are illustrated.Also,drug diffusivity is related to matrix molecular weight.The molecular weight reduction and accumulative drug release within the system are predicted.In order to validate and assess the proposed model,data series of the hydrolytic degradation of aspirin(180.16 Da)-and albumin(66,000 Da)-loaded PLGA(1:1 molar ratio)are used for comparison.The proposed model is in good agreement with experimental data from the literature.Considering diffusion as themain phenomena and autocatalytic effects in the reaction,the drug release profile is predicted.Based on our results for a microneedle containing drug,we are able to estimate drug release rates before fabrication.

pH-activatable oxidative stress amplifying dissolving microneedles for combined chemo-photodynamic therapy of melanoma

Photodynamic therapy(PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation,but the strong hydrophobicity and poor tumor selectivity of photosensitizers,as well as the oxygen-consuming properties of PDT,leading to unsatisfactory therapeutic outcomes.Herein,a tumor acidic microenvironment activatable dissolving microneedle(DHA@HPFe-MN)was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification.The versatile DHA@HPFe-MN was fabricated by crosslinking a self-synthesized protoporphyrin(PpIX)-ADH-hyaluronic acid(HA)conjugate HA-ADH-PpIX with“iron reservoir”PA-Fe 3+complex in the needle tip via acylhydrazone bond formation,and dihydroartemisinin(DHA)was concurrently loaded in the hydrogel network.HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect.DHA@HPFe-MN with sharp needle tip,efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites,where the acidic pH triggered the degradation of microneedles,enabling Fe-activated and DHA-mediated oxidation treatment,as evidenced by abundant reactive oxygen species(ROS)generation.Moreover,under light irradiation,a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation.Importantly,the Fe-catalyzed ROS production of DHA was oxygen-independent,which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells.This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodynamic therapy of melanoma.