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.

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.

Microneedle-based interstitial fluid extraction for drug analysis:Advances,challenges,and prospects

Similar to blood,interstitial fluid(ISF)contains exogenous drugs and biomarkers and may therefore substitute blood in drug analysis.However,current ISF extraction techniques require bulky instruments and are both time-consuming and complicated,which has inspired the development of viable alternatives such as those relying on skin or tissue puncturing with microneedles.Currently,microneedles are widely employed for transdermal drug delivery and have been successfully used for ISF extraction by different mechanisms to facilitate subsequent analysis.The integration of microneedles with sensors enables in situ ISF analysis and specific compound monitoring,while the integration of monitoring and delivery functions in wearable devices allows real-time dose modification.Herein,we review the progress in drug analysis based on microneedle-assisted ISF extraction and discuss the related future opportunities and challenges.

Multidrug dissolvable microneedle patch for the treatment of recurrent oral ulcer

Recurrent oral ulcer is a painful oral mucosal disorder that affects 20%of the world’s population.The lack of a radical cure due to its unknown underlying cause calls for innovative symptomatic treatments.This work reports a hyaluronic acid-based dissolvablemicroneedle patch(ROUMNpatch,short for recurrent oral ulcer microneedle)loaded with dexamethasone acetate,vitamin C and tetracaine hydrochloride for the treatment of recurrent oral ulcers.The ROUMN patch shows enhancement in both the anti-inflammatory effect elicited by dexamethasone and the pro-proliferation effect of vitamin C.In vitro experiments show that ROUMN has a higher efficiency in suppressing lipopolysaccharide(LPS)-induced interleukin-6(IL-6)expression than dexamethasone alone.Cell proliferation and migrationwere also significantly promoted byROUMNcompared to vitamin C alone.The healing-promoting effect of ROUMN was also verified in vivo using an acetic acid-cauterized oral ulcer model in rats.ROUMN as a treatment accelerated the healing process of oral ulcers,shortening the total healing time to 5 days compared with the 7 days required by treatment using watermelon frost,a commonly used over-the-counter(OTC)drug for oral ulcers.The rapid dissolution of the hyaluronic acid-based microneedles and the superior healing-promoting effect of the drug combination could lead to a broad application prospect of the ROUMN patch in the treatment of recurrent oral ulcers.

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.

Hydrogel Microneedle Arrays for Transdermal Drug Delivery

Stratum corneum is the main obstacle for drugs to pass through the skin. Microneedles are composed of arrays of micro-projections formed with different materials, generally ranging from 25-2000 μm in height. Microneedles straightly pierce the skin with its short needle arrays to overcome this barrier. Microneedles can be divided into several categories, for instance, solid microneedles, coated microneedles, and hollow microneedles and so on. However, all these types have their weak points related to corresponding mechanisms.In recent years, pioneering scientists have been working on these issues and some possible solutions have been investigated. This article will focus on the microneedle arrays consisting of hydrogels. Hydrogels are commonly used in drug delivery field. Hydrogel microneedles can be further divided into dissolving and degradable microneedles and phase transition microneedles. The former leaves drug with matrix in the skin. The latter has the feature that drugs in the matrix are delivered while the remaining ingredients can be easily removed from the skin after usage. For drugs which are required to be used every day, the phase transition microneedles are more acceptable. This article is written in order to summarize the advantages of these designs and summarize issues to be solved which may hinder the development of this technology.

Engineering Microneedle Patches for Improved Penetration:Analysis,Skin Models and Factors Affecting Needle Insertion

Transdermal microneedle(MN)patches are a promising tool used to transport a wide variety of active compounds into the skin.To serve as a substitute for common hypodermic needles,MNs must pierce the human stratum corneum(~10 to 20μm),without rupturing or bending during penetration.This ensures that the cargo is released at the predetermined place and time.Therefore,the ability of MN patches to sufficiently pierce the skin is a crucial requirement.In the current review,the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared.This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice.Factors that affect insertion(e.g.,geometry,material composition and cross-linking of MNs),along with recent advancements in developed strategies(e.g.,insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography)to improve the skin penetration are highlighted to provide a backdrop for future research.

V-Shaped Monopole Antenna with Chichena Itzia Inspired Defected Ground Structure for UWB Applications

Due to rapid growth in wireless communication technology,higher bandwidth requirement for advance telecommunication systems,capable of operating on two or higher bands with higher channel capacities and minimum distortion losses is desired.In this paper,a compact Ultra-Wideband(UWB)V-shaped monopole antenna is presented.UWB response is achieved by modifying the ground plane with Chichen Itzia inspired rectangular staircase shape.The proposed V-shaped is designed by incorporating a rectangle,and an inverted isosceles triangle using FR4 substrate.The size of the antenna is 25 mm×26 mm×1.6 mm.The proposed V-shaped monopole antenna produces bandwidth response of 3 GHz Industrial,Scientific,and Medical(ISM),Worldwide Interoperability for Microwave Access(WiMAX),(IEEE 802.11/HIPERLAN band,5G sub 6 GHz)which with an additional square cut amplified the bandwidth response up to 8 GHz ranging from 3.1 GHz to 10.6 GHz attaining UWB defined by Federal Communications Commission(FCC)with a maximum gain of 3.83 dB.The antenna is designed in Ansys HFSS.Results for key performance parameters of the antenna are presented.The measured results are in good agreement with the simulated results.Due to flat gain,uniform group delay,omni directional radiation pattern characteristics and well-matched impedance,the proposed antenna is suitable for WiMAX,ISM and heterogeneous wireless systems.

RIGID-PLASTIC MECHANICAL MODEL FOR THE FORGING METHOD WITH HORIZONTAL V-SHAPED ANVIL

In order to decrease the anisotropy of mechanical properties, the rigid-plastic mechanical model for the forging method with horizontal V-shaped anvil is presented. The forging method, through the change of anvils shape, is able to control fibrous tissue direction, to improve the anisotropy of mechanical properties of axial forgings, to realize uniform forging. Therefore, the forging method can overcome the defect that conventional forging methods produce. The mechanism of the forging method with horizontal V-shaped anvil and the process of metal deformation are analyzed. The agreement of theoretical analysis with experimental study verifies the fact that the forging method with horizontal V-shaped anvil can control effectively the mechanical properties of axial forgings.

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.

An experimental investigation of the fracturing behaviour of rock-like materials containing two V-shaped parallelogram flaws

The distribution characteristics and evolution law of rock mass fissures induced by mining are a key scientific issue in the study of deep rock mechanics.In this study,a series of uniaxial compression experiments was conducted on rock-like specimens containing double V-shaped prefabricated fissures at dip angles ofα=β=45°,α=45°<b=60°,α=β=60°,andα=60°<β=75°with a rock mechanics servocontrolled testing system.According to the experimental results,the effects of the dip angles of the double V-shaped prefabricated flaws with the same area on the mechanical parameters and fracturing process of the specimens were analysed in detail.Additionally,the crack initiation stress presented a nearly linear growth trend,which is generally similar to that of the crack peak stress with increasing flaw dip angle.By applying photographic monitoring to the crack initiation,propagation,coalescence,and failure modes in rock-like specimens,it was easily seen that the V-shaped flaw properties slightly influence the crack initiation positions but significantly influence the crack trajectories.The crack failure modes can be summarized into two distinct types.The study reported herein can provide a better understanding of the evolution of double V-shaped prefabricated fissures induced by coal mining.

Scattering of SH waves induced by a symmetrical V-shaped canyon: a unified analytical solution

This paper reports a series solution of wave functions for two-dimensional scattering and diffraction of plane SH waves induced by a symmetrical V-shaped canyon with different shape ratios. A half-space with a symmetrical V-shaped canyon is divided into two sub-regions by using a circular-arc auxiliary boundary. The two sub-regions are represented by global and local cylindrical coordinate systems, respectively. In each coordinate system, the wave field satisfying the Helmholtz equation is represented by the separation of variables method, in terms of the series of both Bessel functions and Hankel functions with unknown complex coefficients. Then, the two wave fields are described in the local coordinate system using the Graf addition theorem. Finally, the unknown coefficients are sought by satisfying the continuity conditions of the auxiliary boundary. To consider the phase characteristics of the wave scattering, a parametric analysis is carried out in the time domain by assuming an incident signal of the Ricker type. Surface and subsurface transient responses demonstrate the characteristics and mechanisms of wave propagating and scattering.

Depressed Acne Scars—Effective, Minimal Downtime Treatment with a Novel Smooth Motion Non-Insulated Microneedle Radiofrequency Technology

Background: The microneedle fractional RF handpiece used in our study (Intensif Handpiece, EndyMed Medical, Caesarea, Israel) is a novel handpiece that uses a tip with 25 non-insulated, gold plated microneedle electrodes. The needles are inserted into the skin by a specially designed electronically controlled, smooth motion motor minimizing patient discomfort. RF emission delivered over the whole dermal portion of the needle allows effective coagulation resulting in minimal or no bleeding, together with bulk volumetric heating. Study Design/Materials and Methods: The study included 20 patients, treated for depressed acne scars using the IntensifTM?Microneedles handpiece (EndyMed PRO Platform System, EndyMed Medical, Caesarea, Israel). The degree of clinical improvement was assessed by the global aesthetic improvement scale (GAIS) and subjects satisfaction by post treatment questionnaires. Results: The number of treatments per patient varied between 1 and 6 (average 3.3 treatments per patient). Eleven patients (55%) reported none to minimal pain, six (30%) moderate discomfort and only three (15%) reported significant pain. Objective evaluation of the improvement by a board certified dermatologist showed improvement in 95% of patients. 25% showed excellent improvement, 50% experienced good improvement, and the 20% showed minimal improvement. One patient showed no improvement. Conclusions: The presented results show that the tested electronically controlled motorized insertion, non-insulated microneedle treatment technology provides a minimal discomfort, minimal downtime, effective and safe treatment for depressed acne scars.

Design and fabrication of r-hirudin loaded dissolving microneedle patch for minimally invasive and long-term treatment of thromboembolic disease

Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous(SC)and intravenous(IV)administration,but there is a risk of haemorrhage via SC and IV.Thus,microneedle(MN)provides painless and sanitary alternatives to syringes and oral administration.However,the current technological process for the micro mould is complicated and expensive.The micro mould obtained via three-dimensional(3D)printing is expected to save time and cost,as well as provide a diverse range of MNs.Therefore,we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch.The results show that r-hirudin-loaded and hyaluronic acid(HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models.These results indicate that based on 3D printing technology,MNs combined with r-hirudin are expected to achieve diverse customizableMNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.

High‑Performance Flexible Microneedle Array as a Low‑Impedance Surface Biopotential Dry Electrode for Wearable Electrophysiological Recording and Polysomnography

Microneedle array(MNA)electrodes are an effective solution to achieve high-quality surface biopotential recording without the coordination of conductive gel and are thus very suitable for long-term wearable applications.Existing schemes are limited by flexibility,biosafety,and manufacturing costs,which create large barriers for wider applications.Here,we present a novel flexible MNA electrode that can simultaneously achieve flexibility of the substrate to fit a curved body surface,robustness of microneedles to penetrate the skin without fracture,and a simplified process to allow mass production.The compatibility with wearable wireless systems and the short preparation time of the electrodes significantly improves the comfort and convenience of electrophysiological recording.The normalized electrode–skin contact impedance reaches 0.98 kΩcm^(2)at 1 kHz and 1.50 kΩcm^(2)at 10 Hz,a record low value compared to previous reports and approximately 1/250 of the standard electrodes.The morphology,biosafety,and electrical/mechanical properties are fully characterized,and wearable recordings with a high signal-to-noise ratio and low motion artifacts are realized.The first reported clinical study of microneedle electrodes for surface electrophysiological monitoring was conducted in tens of healthy and sleep-disordered subjects with 44 nights of recording(over 8 h per night),providing substantial evidence that the electrodes can be leveraged to substitute for clinical standard electrodes.

Seismic analysis of high-speed railway irregular bridge–track system considering V-shaped canyon effect

To explore the effect of canyon topography on the seismic response of railway irregular bridge-track system that crosses a V-shaped canyon, seismic ground motions of the horizontal site and V-shaped canyon site were simulated through theoretical analysis with 12 earthquake records selected from the Pacific Earthquake Engineering Research Center(PEER) Strong Ground Motion Database matching the site condition of the bridge.Nonlinear seismic response analyses of an existing 11-span irregular simply supported railway bridge-track system were performed under the simulated spatially varying ground motions. The effects of the V-shaped canyon topography on the peak ground acceleration at bridge foundations and seismic responses of the bridge-track system were analyzed. Comparisons between the results of horizontal and V-shaped canyon sites show that the top relative displacement between adjacent piers at the junction of the incident side and the back side of the V-shaped site is almost two times that of the horizontal site, which also determines the seismic response of the fastener. The maximum displacement of the fastener occurs in the V-shaped canyon site and is 1.4 times larger than that in the horizontal site. Neglecting the effect of V-shaped canyon leads to the inappropriate assessment of the maximum seismic response of the irregular high-speed railway bridge-track system. Moreover, engineers should focus on the girder end to the left or right of the two fasteners within the distance of track seismic damage.